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Table of Contents

    Topic review

    UHRF1 in the ECREM Complex

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    Submitted by: Mahmoud Alhosin

    Definition

    The abnormal DNA methylation profiles are transmitted from the cancer mother cell to the daughter cells through the involvement of a macromolecular complex in which the ubiquitin-like containing plant homeodomain (PHD), and an interesting new gene (RING) finger domains 1 (UHRF1), play the role of conductor. Indeed, UHRF1 interacts with epigenetic writers, such as DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a, erasers like histone deacetylase 1 (HDAC1), and functions as a hub protein. Thus, targeting UHRF1 and/or its partners is a promising strategy for epigenetic cancer therapy. The natural compound thymoquinone (TQ) exhibits anticancer activities by targeting several cellular signaling pathways, including those involving UHRF1.

    1. Introduction

    Epigenetic silencing of tumor suppressor genes (TSGs) is considered a main mechanism driving cancer initiation and progression [1][2][3]. Consequently, the reversibility of epigenetic changes has attracted attention and highlighted these changes as interesting targets in the prevention and treatment of cancer. The main epigenetic mechanisms controlling gene expression are DNA methylation and histone post-translational modifications (especially histone deacetylation and methylation), as well as the production of noncoding RNAs. The epigenetic marks left by these modifications are catalyzed by different enzymes, which can act either as writers or erasers [4]. These enzymes work in coordination with another group of epigenetic players, called readers, which are proteins containing specialized domains that can identify and interpret an epigenetic mark in the chromatin structure and can recruit the right writer or eraser to its correct position [4]. One intriguing epigenetic reader is a ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING) finger domains 1 (UHRF1), which can act as a sensor of both types of epigenetic marks (DNA methylation and histone marks) and recruit the corresponding writers, DNA methyltransferase 1 (DNMT1) and G9A, or eraser histone deacetylase 1 (HDAC1), to the right place to catalyze the same epigenetic mark [5][6][7][8][9][10] (Figure 1).
    Figure 1. Role of the epigenetic reader UHRF1 (ubiquitin-like containing plant homeodomain (PHD) and interesting new gene (RING) finger domains 1) in epigenetic silencing of tumor suppressor genes (TSGs). During DNA replication, the SET and RING-associated (SRA) domain of UHRF1 can read methylated CpG sites (hemimethylated DNA) located with TSG promoter. Via the SRA domain, UHRF1 also recruits DNA methyltransferase 1 (DNMT1) and guides it to methylate the unmethylated cytosine of the newly synthetized DNA strand, leading to hypermethylation of the TSG promoter with a global hypomethylation. Through the plant homeodomain (PHD) domain, UHRF1 can bind to unmodified arginine 2 of histone 3 and via its tandem Tudor domain (TTD) domain, UHRF1 can recognize and bind to di or trimethylation of lysine 9 of histone 3 (H3K9me2 or H3K9me3). UHRF1 also uses its SRA domain to recruit histone deacetylase 1 (HDAC1) and recruits histone methyltransferase G9a, leading to histone 3 deacetylation and methylation, respectively. The consequence is the epigenetic silencing of TSGs.
    UHRF1 is an oncogene that is highly expressed in several blood malignancies and solid tumors [11][12][13][14]. It belongs to a large protein complex called the Epigenetic Code Replication Machinery “ECREM” (Figure 2) [12], which is formed through interactions between the different five domains of UHRF1 and several epigenetic writers and erasers (Figure 2) [11][12]. DNMT1, Tat Interacting Protein 60 (Tip60), a histone acetyltransferase, and the histone-lysine N-methyltransferases G9a and Suv39H1, are examples of the epigenetic writers, whereas HDAC1 and herpesvirus-associated ubiquitin-specific protease (HAUSP) serve as epigenetic erasers. The ability of UHRF1 to bind to DNMT1 [15][16][17], HDAC1 [18], Tip60 [19][20] and G9a [21], allows UHRF1 to serve as the master conductor for connecting DNA methylation to histone epigenetic markers (Figure 1) and consequently ensuring their inheritance through cell division [11][12][22]. Through these coordinated interactions, UHRF1 ensures a strong crosstalk between DNA methylation and histone post-transcriptional modifications (especially histone deacetylation and methylation), thereby silencing several TSGs, such as p16INK4A, hMLH1 and BRCA1, throughout successive cell divisions, and facilitating the successful inheritance of the cancer phenotype by the daughter cells [5][11][12]. Interestingly, several studies have reported that either UHRF1 downregulation or targeting its functional domains can act as a trigger that reactivates several TSGs and enables cancer cells to undergo apoptosis, highlighting UHRF1 as a promising target for cancer drug development [23][24][25][26][27][28][29][30][31][32][33][34][35]. Inhibitors of UHRF1 activity and/or expression would conceivably prevent its ability to read the epigenetic markers, thereby also preventing its partners DNMT1, HDCA1 and G9a from acting out their roles as writers or erasers of epigenetic marks. The result of UHRF1 inhibition would, therefore, be the upregulation of the TSGs and subsequent activation of apoptosis pathway.
    Figure 2. Schematic representation of interactions of UHRF1 domains with various epigenetic writers and erasers. UHRF1 uses its SRA domain to interact with DNMT1 [15][16][17] and HDAC1 [18]. UHRF1 can also interact with DNMT1 through PHD [36] and ubiquitin-like domain (UBL) [37][38] domains (black lines). HAUSP (herpes virus-associated ubiquitin-specific protease) interacts with both UHRF1 and DNMT1 [39][40] (red lines). Via its C-terminal region which covers the SRA and RING domains, UHRF1 interacts with histone methyltransferases G9a [21] (blue lines) and histone acetyltransferase Tip60 [19][20]. UHRF1 can interacts with another histone acetyltransferase Suv39H1 [41]. DNMT1 can also interact with Suv39H1 and G9a [42].
    One interesting inhibitor of UHRF1 expression is thymoquinone (TQ), the most abundant biologically active component of black cumin seeds. Many in vitro and in vivo studies have shown that TQ exerts inhibitory effects on a number of different human cancers, including glioblastoma, breast carcinoma, leukemia, and lung, prostate, pancreatic, head and neck, cervical, and liver cancers [43][44][45][46][47][48][49]. TQ exerts its cytotoxic activities against tumor cells by several different mechanisms, including inhibition of cell division, promotion of cell cycle arrest, activation of ROS production, induction of apoptosis and inhibition of tumor angiogenesis and metastasis [50][51]. When compared to its effects on cancer cells, TQ has no or only mild cytotoxic effects on matched normal cells, such as normal human fibroblast cells [52], normal human gastric epithelial cells [53], primary normal neuronal cells [54], normal human astrocytes [55] and normal oral epithelial cells [56]. Although several in vitro and in vivo studies have demonstrated the therapeutic potential of TQ as an anticancer drug for both blood malignancies and solid tumors, there is a lack of clinical studies evaluating TQ in cancer patients. This might be attributed to the poor pharmacokinetics and chemical stability of TQ. Indeed, TQ is heat and light-sensitive, and it has poor solubility in aqueous media, which affects its biodistribution [57][58]. Additionally, covalent binding of TQ to serum albumin, and hepatic metabolism of TQ into hydroquinone, leads to significant loss of anticancer activity after oral administration [57]. To overcome these limitations, TQ could be loaded into nanoscale systems. In this context, TQ-loaded nanoparticles have demonstrated better anticancer activity than free TQ due to enhanced bioavailability and cellular uptake [59].
    Of particular interest to this review is that several studies have now shown that TQ can target the epigenetic reader UHRF1 as well as its partners, the epigenetic writers (DNMT1 and G9A) and erasers like HDAC1 [23][60][61][62][63][64][65][66] (Table 1).
    Table 1. Epigenetic targets of thymoquinone in cancer.

    Epi-Target

    Role of Epi-Target

    Experimental Model

    Mechanisms of Action

    References

    UHRF1

    Reader

    Human cervical carcinoma HeLa cells.

    T-ALL

    TQ targeted the E3 ubiquitin ligase activity of UHRF1 resulting in an auto-ubiquitination of UHRF1 likely through the downregulation of HAUSP

    [23]

    T-ALL

    TQ upregulated p73 expression and cleaved caspase 3 leading to UHRF1 degradation

    [63]

    T-ALL

    TQ decreased the expression of PDE1A leading to the upregulation of p73 and downregulation of UHRF1

    [62]

    T-ALL

    Human breast cancer cells

    TQ decreased the expression of mRNA UHRF1 in dose-dependent mechanism

    [60]

    DNMT1

    DNMT3A

    DNMT3B

    Writer

    Human acute myeloid leukemia cells

    Patient primary cells

    TQ inhibited DNMT1 activity and decreased its expression through the disruption of Sp1/NFkB complex from DNMT1 promoter.

    TQ decreased the expression of DNMT3A through the upregulation of miR-29b, known to directly bind to the 3′-UTR of DNMT3A

    [64]

    T-ALL

    TQ decreased the expression of DNMT1 protein

    [63]

    T-ALL

    TQ decreased the expression of DNMT1, 3A,3B

    [60]

    HDAC1

    HDAC2

    HDAC3

    HDAC4

    HDAC9

    Eraser

    T-ALL

    TQ decreased the expression of HDAC1 protein

    [63]

    T-ALL

    TQ decreased in the expression of HDAC1, 4 and 9

    [60]

    T-ALL

    Human breast cancer cells

    TQ decreased the expression of mRNA HDAC1 in dose-dependent mechanism

    [60]

    Human pancreatic ductal adenocarcinoma cells.

    Human pancreatic ductal adenocarcinoma xenografts.

    TQ inhibited HDAC activity, decreased the expression of HDAC 1, 2, 3 at mRNA levels and increased the acetylation of histone 4 at lysine 12 (H4 Ac-K12)

    [65]

    G9A

    Writer

    T-ALL

    Human breast cancer cells

    TQ decreased the expression of mRNA G9A in dose-dependent mechanism

    [60]

    The TQ-induced inhibition of these epigenetic players is associated with an upregulation of several TSGs that are known to be repressed in several tumors through epigenetic mechanisms. Indeed, TQ can induce the degradation of UHRF1 through a fast autoubiquitination process involving the UHRF1 RING domain, which has a specific E3 ubiquitin ligase activity [23]. Interestingly, UHRF1 ubiquitination was not observed in TQ-treated cells that expressed a mutant form of UHRF1 with a specifically modified RING domain, indicating that the RING domain of UHRF1 undergoes autoubiquitination in response to TQ treatment [23]. Moreover, the deubiquitinase HAUSP, which is known to protect UHRF1 from degradation by the proteasome [39][40], was also downregulated in response to TQ, suggesting that TQ could be the trigger for the autoubiquitination of UHRF1 by an as yet unknown mechanism [23]. Nevertheless, it is absolutely established that the dissociation between HAUSP and UHRF1 is involved.
    An effective epidrug for cancer therapy should consider the epigenetic code as a whole, rather than a single pharmacological target [67][68]. Single epitarget therapies suffer from some significant limitations, particularly the emergence of drug resistance and the triggering of adverse reactions [69]. Identifying compounds with multitargeting properties that are active against epigenetic marks should overcome these limitations. TQ, through its ability to target the expression of both the epigenetic reader UHRF1 and its preferred partners DNMT1, HDAC1 and G9a, is clearly a potential candidate as a multitarget epidrug with the capacity to reverse the epigenetic code of cancer cells as a whole, while allowing the reactivation of TSGs.

    2. Role of the DNMT1/HDAC1/G9a Complex in Epigenetic Silencing of TSGs

    Inactivation of TSGs through epigenetic mechanisms (DNA methylation and histone posttranslational modifications) is one of key factors that promotes the onset of cancer. In cancer cells, the methylation profile is characterized by a global genome hypomethylation, accompanied by a hypermethylation of TSG promoters. The hypermethylation of the CpG islands in TSG promoters, catalyzed by DNMT1, is a significant event in the origin of many cancers [70][71]. Many TSGs, such as RB1, VHL, p16INK4a, BRCA1, HIC-1, MLH1, RUNX3, RASSF1A, FOXO4, PPARG, STK4, PML and KISS1, are silenced in tumors by hypermethylation of their promoters [1][11][12]. TSGs regulate several signaling pathways involved in cell proliferation, the cell cycle, DNA repair, invasion, apoptosis and angiogenesis, all of which are involved in the initiation and/or the development of cancer [11][13].
    Apart from creating an imbalance in DNA methylation, aberrant histone post-translational modifications can also drive the epigenetic inhibition of TSGs in cancers. Aberrant histone post-translational modifications are particularly prevalent in cancer cells [72][73], with post-translational histone modifications usually occurring in the early stages of tumor development and accumulating during tumorigenesis [74][75]. The post-translational modifications occurring at certain sites on histones H3 and H4 are among the most important modifications that exert effects on gene expression [76][77][78]. This modification process is mediated by two types of enzymes with opposite activity: histone acetyltransferases (HATs) and histone deacetylases (HDACs).
    The downregulation or upregulation of HATs is accompanied by tumorigenesis or poor prognosis [79][80]. The Tip60 histone acetyltransferase can acetylate histone proteins, such as histone 2A on lysine 5 (H2AK5) [81], as well as several nonhistone proteins, including p53 and Myc [82], and Tip60 can serve either as an oncogene or as a tumor suppressor [83]. Several tumors, such as skin cancer [84] and osteosarcoma [85], show overexpressed Tip60, whereas other tumors, including lung [86] and breast cancer [87], show low tumor expression levels of Tip60.
    The HDACs, a family of four enzyme subclasses, also have a vital role in tumorigenesis, and are attracting attention due to their contributions to several biological processes, as well as their interactions with other epigenetic enzymes [79]. Changes in HDACs expression in tumors usually result in aberrant deacetylation, leading to activation of TSGs. HDAC1, a class I member, is considered an important epigenetic player mediating histone deacetylation [88][89][90]. HDAC1 is highly expressed in many human tumors, and its overexpression is associated with poor outcomes and tumor progression, thereby identifying this epigenetic eraser as a promising target for cancer therapy [88][91][92][93]. Downregulation of HDAC1 inhibits cell proliferation and cell cycle progression and induces apoptosis in many human tumors, including breast and colon cancer cells, ovarian cancer and lung cancer [90][94][95]. Clinically, HDAC1 overexpression at the mRNA and proteins levels is associated with the clinical features and poor prognosis of patients with breast [96], lung [88] and gastric cancer [97], supporting the idea that the inhibition of HDAC1 activity and/or HDAC1 expression could be a potent strategy for cancer therapy.
    Epigenetic changes involving histone methylation/demethylation are dynamically regulated by two families of enzymes: histone lysine methyltransferases (KMTs) and lysine-specific histone demethylase (KDMs) [98]. Lysine residues can be mono, di or trimethylated, and this process is regulated by the expression levels and the recruitment of KMTs/KDMs to chromatin. The methylation of lysine within histone tails, catalyzed by KMTs, plays a central role in the control of gene transcription [99][100]. G9a, also known as EHMT2 (euchromatic histone-lysine N-methyltransferase 2) and KMT1C (lysine methyltransferase 1C), is one of the major euchromatic methyltransferases [101][102]. The di- or trimethylation of lysine 9 of histone 3 (H3K9me2 or H3K9me3) mediated by the KMT G9a is considered one of histone changes with a known role in gene silencing, whereas the methylation of lysine 4 (H3K4me) on the same histone is related to gene activation [103][104]. Several studies have shown that G9a is overexpressed in a panel of human cancers, and that its high expression levels are associated with unfavorable clinicopathological parameters and poor survival [105][106][107][108]. Interestingly, the depletion of G9a is sufficient to induce a reactivation of TSGs and inhibition of cancer cell proliferation [109][110][111].
    Several other studies have also reported a coordinated activity between several epigenetic factors, including DNMT1, HDAC1, G91 and Suv39H1, during DNA synthesis that maintains the transmission of the epigenetic code [42][112][113][114][115][116]. In this context, DNMT1 was shown to physically interact with both the H3K9 histone methyltransferases G9a and Suv39H1 [42]. DNMT1 colocalized with G9a at replication foci during DNA replication, while DNMT1 colocalized with Suv39H1 on heterochromatic regions predominantly before cell division [42]. The DNMT1/HDAC1/Suv39H1 complex, in coordination with other factors, was found to regulate the expression of the estrogen receptor-a (ER) in breast cancer cells [116].
    A key remaining question is whether a principal conductor exists that coordinates all these epigenetic factors to orchestrate the precise timing of the recruitment of the correct enzyme to its right place. In this review, we propose that UHRF1 is a likely candidate. Based on its structure and its multiple interactions with several writers and erasers, UHRF1 can direct coordinated crosstalk between DNA methylation and histone posttranslational modifications, thereby making it a probable candidate as the leader in the ECREM complex.

    3. A master Role for UHRF1 in the ECREM Complex Driving Epigenetic Inhibition of TSGs

    In tumors, no clear mechanisms are yet identified that explain the maintenance of the inheritance of a silenced TSG from a mother cancer cell to the daughter cells during cell division. However, the functioning of UHRF1 as the conductor and hub protein in its complex could ensure this transmission during cell division [5][6][12][14][15][16][20][22][36][78]. Indeed, several in vitro and in vivo studies have reported the detection of UHRF1 overexpression in many human cancers, and that this overexpression is a crucial factor in the epigenetic silencing of various TSGs and leads to enhanced cell proliferation, cell cycle progression, and suppression of apoptosis [11][12]. UHRF1 uses its different domain functions to repress the expression of TSGs through several mechanisms that involve TSG promoter hypermethylation via the physical interaction with DNMT1, HDAC1-mediated histone deacetylation, and G9a-catalyzed histone 3 methylation [11][12] (Figure 1).
    The induction of TSGs silencing is well documented to occur by hypermethylation of CpG islands located within TSGs promoters. However, the mechanisms by which the CpG islands are specifically targeted is still unclear. One hypothesis is that the hypermethylation of the CpG islands in the TSG promoters is driven by a mechanism involving a protein that can bind to DNA and guide DNMT1 to its correct place at the right time during DNA replication. UHRF1 is a likely candidate because of its high affinity for hemimethylated vs. nonmethylated DNA [117], and its direct interaction with DNMT1 [15][16][17][36]. These capabilities give UHRF1 the necessary duality to allow the successful transfer of DNA methylation patterns, including the hypermethylation of TSGs. During DNA replication, the SRA domain of UHRF1 can recognize methylated CpG sites (hemimethylated DNA) by flipping out the methylated cytosine. In addition, via the same domain, UHRF1 can recruit DNMT1 and guide it to methylate the unmethylated cytosine of the newly synthetized DNA strand [117] (Figure 1). UHRF1 can also interact with DNMT1 through its PHD domain [36] and UBL domain [37][38] (Figure 2). Beside the role of SRA domain of UHRF1 in the binding to hemimethylated DNA and the recruitment of DNMT1 to sites of methylation DNA [117], UHRF1 has a well-established role through its RING domain in the ubiquitylation of H3 and DNMT1, targeting for sites of hemimethylated DNA [118][119]. Indeed, UHRF1 uses the ubiquitin ligase activity of its RING domain to ubiquitinate H3. The reading and writing this epigenetic mark (H3 ubiquitination) by UHRF1 is a prerequisite for the binding of DNMT1 to ubiquitylated histone H3 [120] to ensure a faithful recruitment of DNMT1 to sites of hemimethylated DNA [22][118][119]. Moreover, the recruitment of DNMT1 to DNA methylation sites is also regulated by H3 deubiquitylation through a mechanism involves HAUSP, another member of ECREM complex [121]. HAUSP was shown to interact with DNMT1 and is recruited to sites of DNA methylation during DNA replication, and this recruitment requires UHRF1 [121]. HAUSP induced the deubiquitylation of ubiquitylated histone H3 in vitro, while HAUSP depletion in cancer cells resulted in enhanced histone H3 ubiquitylation [121]. This suggests that HAUSP has a key role in the regulation of maintenance of DNA methylation through UHRF1-dependent deubiquitylation of ubiquitylated histone H3. However, HAUSP and DNMT1 appear to behave as independent proteins at replication foci, since global DNA methylation levels were not notably altered in cells with HAUSP knockout [122][123].
    Several works have shown that both histone methylation and acetylation work together with DNA methylation to exert inhibitory effects on the expression of TSGs in cancer cells through mechanisms that remain incompletely understood [124][125][126][127][128]. Through its SRA domain, UHRF1 can directly bind to HDAC1 and recruit it to methylated promoter regions of the TSGs p16INK4A and p14ARF, resulting in their silencing by a histone deacetylation process [18]. In the same context, renal cell carcinoma (RCC) tumors show high expression levels of UHRF1 compared to normal renal tissues, and this overexpression is associated with a decreased expression of the tumor suppressor gene TXNIP [129]. UHRF1 was shown to recruit HDAC1 to the TXNIP gene promoter and mediate the deacetylation of histone H3 on the lysine 9 (H3K9), resulting in an epigenetic inhibition of TXNIP expression [129]. Interestingly, UHRF1 downregulation in RCC cell lines induced the upregulation of TXNIP expression and apoptosis, suggesting that UHRF1 inhibits the expression of TXNIP in RCC through epigenetic mechanisms, thereby promoting tumor progression [129].
    The UHRF1/HAUSP/DNMT1 complex was also detected on the promoters of HHIP and IGFBP3, two key TSGs in hepatoblastoma, and this interaction caused the inhibition of these genes [130]. Silencing of HHIP and IGFBP3 genes was associated with an increase in the dimethylation of histone 3 on lysine 9 (H3K9me2) [130], which is a well-documented repression mark in cancer [131][132]. Interestingly, the depletion of UHRF1, but not of its partner HAUSP, significantly increased the expression of the HHIP and IGFBP3 genes and decreased the H3K9me2 mark at the HHIP and IGFBP3 TSG loci, leading to the inhibition of hepatoblastoma cell growth [130]. Similarly, UHRF1 was also shown to recruit DNMT1 to the promoter of the tumor suppressor gene BRCA1 leading to BRCA1 inhibition through methylation of its promoter [133]. Besides guiding DNMT1, UHRF1 also recruited HDAC1 and G9a to the BRCA1 loci, resulting in histone 3 deacetylation and methylation, respectively, and facilitating the silencing of BRCA1 [133].
    Taken together, the findings of these studies support the idea that UHRF1 overexpression is one of the primary causes of cancer pathogenesis, and that UHRF1 exerts direct inhibitory effects on various TSGs through a coordinated recruitment of several epigenetic players, namely DNMT1, HDAC1 and G9a, to their correct places on the chromatin to catalyze the right epigenetic mark (Figure 1). These studies also reinforce the view that DNMT1, HDAC1 and G91 might coregulate the expression of TSGs in cancer, and that this process is directly under the control of the epigenetic reader UHRF1 (Figure 1). Thus, understanding the role of the UHRF1/DNMT1/HDAC1/G9a complex in reading the epigenetic marks (DNA methylation and histone marks) in cancer will allow the development of a new generation of multitarget epidrugs. These drug candidates may have value in targeting UHRF1 as the principal conductor, with subsequent regulatory effects on the other partners, DNMT1, HDAC1 and G91.

    4. UHRF1 Is a Main Target of Natural Compounds Exhibiting Anticancer Properties

    UHRF1 has been reported to be a target of several natural compounds or derivatives that exhibit anticancer properties by downregulating UHRF1. These compounds include TQ [11][12][23][60][61][62][63], curcumin [134], epigallocatechin-3-gallate [24][135], anisomycin [136], dihydroartemisinin [40], emodin [137], hinokitiol [33], shikonin [138], and luteolin [139][140], which can all upregulate many TSGs. Of these natural products, epigallocatechin-3-gallate and TQ have been shown to specifically target the SRA and RING domains of UHRF1, respectively. Our previous work revealed that epigallocatechin-3-gallate (EGCG) induced cell cycle arrest and apoptosis in Jurkat cells by the downregulation of UHRF1 and DNMT1, and the upregulation of the tumor suppressor p16INK4A [24]. A significant decrease in UHRF1 binding to the p16INK4A promoter was detected in response to EGCG but not in nontreated Jurkat cells. Overexpression of wild-type UHRF1 decreased the p16INK4A protein expression in the presence of EGCG, but the overexpression of UHRF1 mutations that specifically targeted two regions of the UNRF1 SRA domain did not decrease p16INK4A expression, indicating that UHRF1 requires a functional SRA domain to bind DNA and recruit DNMT1 to chromatin [24]. We also found that TQ induces auto-ubiquitination of UHRF1 and subsequent degradation in cancer cells [23] by targeting its RING domain, which is the only domain of the UHRF1 structure that exhibits enzymatic activity [5][141].

    The entry is from 10.3390/genes12050622

    References

    1. Baylin, S.B.; Jones, P.A. Epigenetic Determinants of Cancer. Cold Spring Harb. Perspect. Biol. 2016, 8, a019505.
    2. Wu, Y.; Sarkissyan, M.; Vadgama, J.V. Epigenetics in breast and prostate cancer. Methods Mol. Biol. 2015, 1238, 425–466.
    3. Lomberk, G.A. Epigenetic silencing of tumor suppressor genes in pancreatic cancer. J. Gastrointest. Cancer 2011, 42, 93–99.
    4. Biswas, S.; Rao, C.M. Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy. Eur. J. Pharmacol. 2018, 837, 8–24.
    5. Bronner, C.; Krifa, M.; Mousli, M. Increasing role of UHRF1 in the reading and inheritance of the epigenetic code as well as in tumorogenesis. Biochem. Pharmacol. 2013, 86, 1643–1649.
    6. Houliston, R.S.; Lemak, A.; Iqbal, A.; Ivanochko, D.; Duan, S.; Kaustov, L.; Ong, M.S.; Fan, L.; Senisterra, G.; Brown, P.J.; et al. Conformational dynamics of the TTD-PHD histone reader module of the UHRF1 epigenetic regulator reveals multiple histone-binding states, allosteric regulation, and druggability. J. Biol. Chem. 2017, 292, 20947–20959.
    7. Abhishek, S.; Nivya, M.A.; Nakarakanti, N.K.; Deeksha, W.; Khosla, S.; Rajakumara, E. Biochemical and dynamic basis for combinatorial recognition of H3R2K9me2 by dual domains of UHRF1. Biochimie 2018, 149, 105–114.
    8. Arita, K.; Isogai, S.; Oda, T.; Unoki, M.; Sugita, K.; Sekiyama, N.; Kuwata, K.; Hamamoto, R.; Tochio, H.; Sato, M.; et al. Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc. Natl. Acad. Sci. USA 2012, 109, 12950–12955.
    9. Kilin, V.; Gavvala, K.; Barthes, N.P.; Michel, B.Y.; Shin, D.; Boudier, C.; Mauffret, O.; Yashchuk, V.; Mousli, M.; Ruff, M.; et al. Dynamics of Methylated Cytosine Flipping by UHRF1. J. Am. Chem. Soc. 2017, 139, 2520–2528.
    10. Schneider, M.; Trummer, C.; Stengl, A.; Zhang, P.; Szwagierczak, A.; Cardoso, M.C.; Leonhardt, H.; Bauer, C.; Antes, I. Systematic analysis of the binding behaviour of UHRF1 towards different methyl- and carboxylcytosine modification patterns at CpG dyads. PLoS ONE 2020, 15, e0229144.
    11. Alhosin, M.; Omran, Z.; Zamzami, M.A.; Al-Malki, A.L.; Choudhry, H.; Mousli, M.; Bronner, C. Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer. J. Exp. Clin. Cancer Res. CR 2016, 35, 174.
    12. Alhosin, M.; Sharif, T.; Mousli, M.; Etienne-Selloum, N.; Fuhrmann, G.; Schini-Kerth, V.B.; Bronner, C. Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. J. Exp. Clin. Cancer Res. CR 2011, 30, 41.
    13. Ashraf, W.; Ibrahim, A.; Alhosin, M.; Zaayter, L.; Ouararhni, K.; Papin, C.; Ahmad, T.; Hamiche, A.; Mély, Y.; Bronner, C.; et al. The epigenetic integrator UHRF1: On the road to become a universal biomarker for cancer. Oncotarget 2017, 8, 51946–51962.
    14. Sidhu, H.; Capalash, N. UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2017, 39, 1010428317692205.
    15. Achour, M.; Jacq, X.; Rondé, P.; Alhosin, M.; Charlot, C.; Chataigneau, T.; Jeanblanc, M.; Macaluso, M.; Giordano, A.; Hughes, A.D.; et al. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene 2008, 27, 2187–2197.
    16. Hashimoto, H.; Horton, J.R.; Zhang, X.; Bostick, M.; Jacobsen, S.E.; Cheng, X. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 2008, 455, 826–829.
    17. Sharif, J.; Muto, M.; Takebayashi, S.; Suetake, I.; Iwamatsu, A.; Endo, T.A.; Shinga, J.; Mizutani-Koseki, Y.; Toyoda, T.; Okamura, K.; et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 2007, 450, 908–912.
    18. Unoki, M.; Nishidate, T.; Nakamura, Y. ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 2004, 23, 7601–7610.
    19. Ashraf, W.; Bronner, C.; Zaayter, L.; Ahmad, T.; Richert, L.; Alhosin, M.; Ibrahim, A.; Hamiche, A.; Mely, Y.; Mousli, M. Interaction of the epigenetic integrator UHRF1 with the MYST domain of TIP60 inside the cell. J. Exp. Clin. Cancer Res. CR 2017, 36, 188.
    20. Achour, M.; Fuhrmann, G.; Alhosin, M.; Rondé, P.; Chataigneau, T.; Mousli, M.; Schini-Kerth, V.B.; Bronner, C. UHRF1 recruits the histone acetyltransferase Tip60 and controls its expression and activity. Biochem. Biophys. Res. Commun. 2009, 390, 523–528.
    21. Kim, J.K.; Estève, P.O.; Jacobsen, S.E.; Pradhan, S. UHRF1 binds G9a and participates in p21 transcriptional regulation in mammalian cells. Nucleic Acids Res. 2009, 37, 493–505.
    22. Bronner, C.; Alhosin, M.; Hamiche, A.; Mousli, M. Coordinated Dialogue between UHRF1 and DNMT1 to Ensure Faithful Inheritance of Methylated DNA Patterns. Genes 2019, 10, 65.
    23. Ibrahim, A.; Alhosin, M.; Papin, C.; Ouararhni, K.; Omran, Z.; Zamzami, M.A.; Al-Malki, A.L.; Choudhry, H.; Mély, Y.; Hamiche, A.; et al. Thymoquinone challenges UHRF1 to commit auto-ubiquitination: A key event for apoptosis induction in cancer cells. Oncotarget 2018, 9, 28599–28611.
    24. Achour, M.; Mousli, M.; Alhosin, M.; Ibrahim, A.; Peluso, J.; Muller, C.D.; Schini-Kerth, V.B.; Hamiche, A.; Dhe-Paganon, S.; Bronner, C. Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1. Biochem. Biophys. Res. Commun. 2013, 430, 208–212.
    25. Liu, X.; Ou, H.; Xiang, L.; Li, X.; Huang, Y.; Yang, D. Elevated UHRF1 expression contributes to poor prognosis by promoting cell proliferation and metastasis in hepatocellular carcinoma. Oncotarget 2017, 8, 10510–10522.
    26. Wang, B.C.; Lin, G.H.; Wang, B.; Yan, M.; He, B.; Zhang, W.; Yang, A.K.; Long, Z.J.; Liu, Q. UHRF1 suppression promotes cell differentiation and reduces inflammatory reaction in anaplastic thyroid cancer. Oncotarget 2018, 9, 31945–31957.
    27. Yang, C.; Li, J.; Yu, L.; Zhang, Z.; Xu, F.; Jiang, L.; Zhou, X.; He, S. Regulation of RIP3 by the transcription factor Sp1 and the epigenetic regulator UHRF1 modulates cancer cell necroptosis. Cell Death Dis. 2017, 8, e3084.
    28. Ge, T.T.; Yang, M.; Chen, Z.; Lou, G.; Gu, T. UHRF1 gene silencing inhibits cell proliferation and promotes cell apoptosis in human cervical squamous cell carcinoma CaSki cells. J. Ovarian Res. 2016, 9, 42.
    29. Matsushita, R.; Yoshino, H.; Enokida, H.; Goto, Y.; Miyamoto, K.; Yonemori, M.; Inoguchi, S.; Nakagawa, M.; Seki, N. Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): Inhibition of bladder cancer cell aggressiveness. Oncotarget 2016, 7, 28460–28487.
    30. Wan, X.; Yang, S.; Huang, W.; Wu, D.; Chen, H.; Wu, M.; Li, J.; Li, T.; Li, Y. UHRF1 overexpression is involved in cell proliferation and biochemical recurrence in prostate cancer after radical prostatectomy. J. Exp. Clin. Cancer Res. CR 2016, 35, 34.
    31. Qin, Y.; Wang, J.; Gong, W.; Zhang, M.; Tang, Z.; Zhang, J.; Quan, Z. UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest. Oncol. Rep. 2014, 31, 2635–2643.
    32. Niinuma, T.; Kitajima, H.; Kai, M.; Yamamoto, E.; Yorozu, A.; Ishiguro, K.; Sasaki, H.; Sudo, G.; Toyota, M.; Hatahira, T.; et al. UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells. Clin. Epigenet. 2019, 11, 70.
    33. Seo, J.S.; Choi, Y.H.; Moon, J.W.; Kim, H.S.; Park, S.H. Hinokitiol induces DNA demethylation via DNMT1 and UHRF1 inhibition in colon cancer cells. BMC Cell Biol. 2017, 18, 14.
    34. Gao, S.P.; Sun, H.F.; Li, L.D.; Fu, W.Y.; Jin, W. UHRF1 promotes breast cancer progression by suppressing KLF17 expression by hypermethylating its promoter. Am. J. Cancer Res. 2017, 7, 1554–1565.
    35. Zhang, Q.; Qiao, L.; Wang, X.; Ding, C.; Chen, J.J. UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells. Cell Cycle 2018, 17, 300–308.
    36. Bostick, M.; Kim, J.K.; Estève, P.O.; Clark, A.; Pradhan, S.; Jacobsen, S.E. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 2007, 317, 1760–1764.
    37. Foster, B.M.; Stolz, P.; Mulholland, C.B.; Montoya, A.; Kramer, H.; Bultmann, S.; Bartke, T. Critical Role of the UBL Domain in Stimulating the E3 Ubiquitin Ligase Activity of UHRF1 toward Chromatin. Mol. Cell 2018, 72, 739–752.e9.
    38. Li, T.; Wang, L.; Du, Y.; Xie, S.; Yang, X.; Lian, F.; Zhou, Z.; Qian, C. Structural and mechanistic insights into UHRF1-mediated DNMT1 activation in the maintenance DNA methylation. Nucleic Acids Res. 2018, 46, 3218–3231.
    39. Felle, M.; Joppien, S.; Németh, A.; Diermeier, S.; Thalhammer, V.; Dobner, T.; Kremmer, E.; Kappler, R.; Längst, G. The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1. Nucleic Acids Res. 2011, 39, 8355–8365.
    40. Du, S.; Xu, G.; Zou, W.; Xiang, T.; Luo, Z. Effect of dihydroartemisinin on UHRF1 gene expression in human prostate cancer PC-3 cells. Anti-Cancer Drugs 2017, 28, 384–391.
    41. Babbio, F.; Pistore, C.; Curti, L.; Castiglioni, I.; Kunderfranco, P.; Brino, L.; Oudet, P.; Seiler, R.; Thalman, G.N.; Roggero, E.; et al. The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression. Oncogene 2012, 31, 4878–4887.
    42. Estève, P.O.; Chin, H.G.; Smallwood, A.; Feehery, G.R.; Gangisetty, O.; Karpf, A.R.; Carey, M.F.; Pradhan, S. Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev. 2006, 20, 3089–3103.
    43. Darakhshan, S.; Bidmeshki Pour, A.; Hosseinzadeh Colagar, A.; Sisakhtnezhad, S. Thymoquinone and its therapeutic potentials. Pharmacol. Res. 2015, 95–96, 138–158.
    44. Khan, M.A.; Tania, M.; Fu, J. Epigenetic role of thymoquinone: Impact on cellular mechanism and cancer therapeutics. Drug Discov. Today 2019, 24, 2315–2322.
    45. Mahmoud, Y.K.; Abdelrazek, H.M.A. Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy. Biomed. Pharmacother. Biomed. Pharmacother. 2019, 115, 108783.
    46. Shanmugam, M.K.; Ahn, K.S.; Hsu, A.; Woo, C.C.; Yuan, Y.; Tan, K.H.B.; Chinnathambi, A.; Alahmadi, T.A.; Alharbi, S.A.; Koh, A.P.F.; et al. Thymoquinone Inhibits Bone Metastasis of Breast Cancer Cells Through Abrogation of the CXCR4 Signaling Axis. Front. Pharmacol. 2018, 9, 1294.
    47. Lee, Y.M.; Kim, G.H.; Park, E.J.; Oh, T.I.; Lee, S.; Kan, S.Y.; Kang, H.; Kim, B.M.; Kim, J.H.; Lim, J.H. Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis. Int. J. Mol. Sci. 2019, 20, 1092.
    48. Zhang, Y.; Fan, Y.; Huang, S.; Wang, G.; Han, R.; Lei, F.; Luo, A.; Jing, X.; Zhao, L.; Gu, S.; et al. Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci. 2018, 109, 3865–3873.
    49. Ndreshkjana, B.; Çapci, A.; Klein, V.; Chanvorachote, P.; Muenzner, J.K.; Huebner, K.; Steinmann, S.; Erlenbach-Wuensch, K.; Geppert, C.I.; Agaimy, A.; et al. Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells. Cell Death Dis. 2019, 10, 379.
    50. Goyal, S.N.; Prajapati, C.P.; Gore, P.R.; Patil, C.R.; Mahajan, U.B.; Sharma, C.; Talla, S.P.; Ojha, S.K. Therapeutic Potential and Pharmaceutical Development of Thymoquinone: A Multitargeted Molecule of Natural Origin. Front. Pharmacol. 2017, 8, 656.
    51. Woo, C.C.; Kumar, A.P.; Sethi, G.; Tan, K.H. Thymoquinone: Potential cure for inflammatory disorders and cancer. Biochem. Pharmacol. 2012, 83, 443–451.
    52. Alhosin, M.; Ibrahim, A.; Boukhari, A.; Sharif, T.; Gies, J.P.; Auger, C.; Schini-Kerth, V.B. Anti-neoplastic agent thymoquinone induces degradation of α and β tubulin proteins in human cancer cells without affecting their level in normal human fibroblasts. Investig. New Drugs 2012, 30, 1813–1819.
    53. Feng, L.M.; Wang, X.F.; Huang, Q.X. Thymoquinone induces cytotoxicity and reprogramming of EMT in gastric cancer cells by targeting PI3K/Akt/mTOR pathway. J. Biosci. 2017, 42, 547–554.
    54. Paramasivam, A.; Raghunandhakumar, S.; Priyadharsini, J.V.; Jayaraman, G. In Vitro Anti-Neuroblastoma Activity of Thymoquinone against Neuro-2a Cells via Cell-cycle Arrest. Asian Pac. J. Cancer Prev. APJCP 2015, 16, 8313–8319.
    55. Racoma, I.O.; Meisen, W.H.; Wang, Q.E.; Kaur, B.; Wani, A.A. Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS ONE 2013, 8, e72882.
    56. Alaufi, O.M.; Noorwali, A.; Zahran, F.; Al-Abd, A.M.; Al-Attas, S. Cytotoxicity of thymoquinone alone or in combination with cisplatin (CDDP) against oral squamous cell carcinoma in vitro. Sci. Rep. 2017, 7, 13131.
    57. Abukhader, M.M. Thymoquinone in the clinical treatment of cancer: Fact or fiction? Pharmacogn. Rev. 2013, 7, 117–120.
    58. Odeh, F.; Ismail, S.I.; Abu-Dahab, R.; Mahmoud, I.S.; Al Bawab, A. Thymoquinone in liposomes: A study of loading efficiency and biological activity towards breast cancer. Drug Deliv. 2012, 19, 371–377.
    59. Ganea, G.M.; Fakayode, S.O.; Losso, J.N.; van Nostrum, C.F.; Sabliov, C.M.; Warner, I.M. Delivery of phytochemical thymoquinone using molecular micelle modified poly(D, L lactide-co-glycolide) (PLGA) nanoparticles. Nanotechnology 2010, 21, 285104.
    60. Qadi, S.A.; Hassan, M.A.; Sheikh, R.A.; Baothman, O.A.; Zamzami, M.A.; Choudhry, H.; Al-Malki, A.L.; Albukhari, A.; Alhosin, M. Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms. Epigenetics Insights 2019, 12, 2516865719839011.
    61. Alhosin, M.; Razvi, S.S.I.; Sheikh, R.A.; Khan, J.A.; Zamzami, M.A.; Choudhry, H. Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways. Technol. Cancer Res. Treat. 2020, 19, 1533033820947489.
    62. Abusnina, A.; Alhosin, M.; Keravis, T.; Muller, C.D.; Fuhrmann, G.; Bronner, C.; Lugnier, C. Down-regulation of cyclic nucleotide phosphodiesterase PDE1A is the key event of p73 and UHRF1 deregulation in thymoquinone-induced acute lymphoblastic leukemia cell apoptosis. Cell. Signal. 2011, 23, 152–160.
    63. Alhosin, M.; Abusnina, A.; Achour, M.; Sharif, T.; Muller, C.; Peluso, J.; Chataigneau, T.; Lugnier, C.; Schini-Kerth, V.B.; Bronner, C.; et al. Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1. Biochem. Pharmacol. 2010, 79, 1251–1260.
    64. Pang, J.; Shen, N.; Yan, F.; Zhao, N.; Dou, L.; Wu, L.C.; Seiler, C.L.; Yu, L.; Yang, K.; Bachanova, V.; et al. Thymoquinone exerts potent growth-suppressive activity on leukemia through DNA hypermethylation reversal in leukemia cells. Oncotarget 2017, 8, 34453–34467.
    65. Relles, D.; Chipitsyna, G.I.; Gong, Q.; Yeo, C.J.; Arafat, H.A. Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation. Adv. Prev. Med. 2016, 2016, 1407840.
    66. Parbin, S.; Shilpi, A.; Kar, S.; Pradhan, N.; Sengupta, D.; Deb, M.; Rath, S.K.; Patra, S.K. Insights into the molecular interactions of thymoquinone with histone deacetylase: Evaluation of the therapeutic intervention potential against breast cancer. Mol. Biosyst. 2016, 12, 48–58.
    67. Benedetti, R.; Conte, M.; Iside, C.; Altucci, L. Epigenetic-based therapy: From single- to multi-target approaches. Int. J. Biochem. Cell Biol. 2015, 69, 121–131.
    68. Ganesan, A. Multitarget Drugs: An Epigenetic Epiphany. ChemMedChem 2016, 11, 1227–1241.
    69. Tomaselli, D.; Lucidi, A.; Rotili, D.; Mai, A. Epigenetic polypharmacology: A new frontier for epi-drug discovery. Med. Res. Rev. 2020, 40, 190–244.
    70. Jones, P.A.; Baylin, S.B. The epigenomics of cancer. Cell 2007, 128, 683–692.
    71. Jones, P.A.; Liang, G. Rethinking how DNA methylation patterns are maintained. Nat. Rev. Genet. 2009, 10, 805–811.
    72. Seligson, D.B.; Horvath, S.; Shi, T.; Yu, H.; Tze, S.; Grunstein, M.; Kurdistani, S.K. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005, 435, 1262–1266.
    73. Ben-Porath, I.; Cedar, H. Epigenetic crosstalk. Mol. Cell 2001, 8, 933–935.
    74. Cheng, Y.; He, C.; Wang, M.; Ma, X.; Mo, F.; Yang, S.; Han, J.; Wei, X. Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials. Signal Transduct. Target. Ther. 2019, 4, 62.
    75. Fraga, M.F.; Ballestar, E.; Villar-Garea, A.; Boix-Chornet, M.; Espada, J.; Schotta, G.; Bonaldi, T.; Haydon, C.; Ropero, S.; Petrie, K.; et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 2005, 37, 391–400.
    76. Kouzarides, T. Chromatin modifications and their function. Cell 2007, 128, 693–705.
    77. Vaissière, T.; Sawan, C.; Herceg, Z. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat. Res. 2008, 659, 40–48.
    78. Bronner, C.; Fuhrmann, G.; Chédin, F.L.; Macaluso, M.; Dhe-Paganon, S. UHRF1 Links the Histone code and DNA Methylation to ensure Faithful Epigenetic Memory Inheritance. Genet. Epigenetics 2010, 2009, 29–36.
    79. Seligson, D.B.; Horvath, S.; McBrian, M.A.; Mah, V.; Yu, H.; Tze, S.; Wang, Q.; Chia, D.; Goodglick, L.; Kurdistani, S.K. Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol. 2009, 174, 1619–1628.
    80. Chen, Y.F.; Luo, R.Z.; Li, Y.; Cui, B.K.; Song, M.; Yang, A.K.; Chen, W.K. High expression levels of COX-2 and P300 are associated with unfavorable survival in laryngeal squamous cell carcinoma. Eur. Arch. Otorhinolaryngol. 2013, 270, 1009–1017.
    81. Kimura, A.; Horikoshi, M. Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells Devoted Mol. Cell. Mech. 1998, 3, 789–800.
    82. Gorrini, C.; Squatrito, M.; Luise, C.; Syed, N.; Perna, D.; Wark, L.; Martinato, F.; Sardella, D.; Verrecchia, A.; Bennett, S.; et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 2007, 448, 1063–1067.
    83. Judes, G.; Rifaï, K.; Ngollo, M.; Daures, M.; Bignon, Y.J.; Penault-Llorca, F.; Bernard-Gallon, D. A bivalent role of TIP60 histone acetyl transferase in human cancer. Epigenomics 2015, 7, 1351–1363.
    84. Stacy, A.J.; Zhang, J.; Craig, M.P.; Hira, A.; Dole, N.; Kadakia, M.P. TIP60 up-regulates ΔNp63α to promote cellular proliferation. J. Biol. Chem. 2019, 294, 17007–17016.
    85. Shi, X.; Fan, M. Tip60-dependent acetylation of KDM2B promotes osteosarcoma carcinogenesis. J. Cell. Mol. Med. 2019, 23, 6154–6163.
    86. Yang, Y.; Sun, J.; Chen, T.; Tao, Z.; Zhang, X.; Tian, F.; Zhou, X.; Lu, D. Tat-interactive Protein-60KDA (TIP60) Regulates the Tumorigenesis of Lung Cancer In Vitro. J. Cancer 2017, 8, 2277–2281.
    87. Judes, G.; Dubois, L.; Rifaï, K.; Idrissou, M.; Mishellany, F.; Pajon, A.; Besse, S.; Daures, M.; Degoul, F.; Bignon, Y.J.; et al. TIP60: An actor in acetylation of H3K4 and tumor development in breast cancer. Epigenomics 2018, 10, 1415–1430.
    88. Cao, L.L.; Song, X.; Pei, L.; Liu, L.; Wang, H.; Jia, M. Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer: A meta-analysis. Medicine 2017, 96, e7663.
    89. Phi van, D.K.; Mühlbauer, E.; Phi-van, L. Histone deacetylase HDAC1 downregulates transcription of the serotonin transporter (5-HTT) gene in tumor cells. Biochim. Biophys. Acta 2015, 1849, 909–918.
    90. Liu, X.; Yu, Y.; Zhang, J.; Lu, C.; Wang, L.; Liu, P.; Song, H. HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 2018, 48, 1505–1518.
    91. Barneda-Zahonero, B.; Parra, M. Histone deacetylases and cancer. Mol. Oncol. 2012, 6, 579–589.
    92. Fritzsche, F.R.; Weichert, W.; Röske, A.; Gekeler, V.; Beckers, T.; Stephan, C.; Jung, K.; Scholman, K.; Denkert, C.; Dietel, M.; et al. Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer 2008, 8, 381.
    93. Weichert, W.; Röske, A.; Niesporek, S.; Noske, A.; Buckendahl, A.C.; Dietel, M.; Gekeler, V.; Boehm, M.; Beckers, T.; Denkert, C. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: Specific role of class I histone deacetylases in vitro and in vivo. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2008, 14, 1669–1677.
    94. Senese, S.; Zaragoza, K.; Minardi, S.; Muradore, I.; Ronzoni, S.; Passafaro, A.; Bernard, L.; Draetta, G.F.; Alcalay, M.; Seiser, C.; et al. Role for histone deacetylase 1 in human tumor cell proliferation. Mol. Cell. Biol. 2007, 27, 4784–4795.
    95. Zhang, L.; Bu, L.; Hu, J.; Xu, Z.; Ruan, L.; Fang, Y.; Wang, P. HDAC1 knockdown inhibits invasion and induces apoptosis in non-small cell lung cancer cells. Biol. Chem. 2018, 399, 603–610.
    96. Krusche, C.A.; Wülfing, P.; Kersting, C.; Vloet, A.; Böcker, W.; Kiesel, L.; Beier, H.M.; Alfer, J. Histone deacetylase-1 and -3 protein expression in human breast cancer: A tissue microarray analysis. Breast Cancer Res. Treat. 2005, 90, 15–23.
    97. Wisnieski, F.; Calcagno, D.Q.; Leal, M.F.; Chen, E.S.; Gigek, C.O.; Santos, L.C.; Pontes, T.B.; Rasmussen, L.T.; Payão, S.L.; Assumpção, P.P.; et al. Differential expression of histone deacetylase and acetyltransferase genes in gastric cancer and their modulation by trichostatin A. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 2014, 35, 6373–6381.
    98. Shi, Y.; Lan, F.; Matson, C.; Mulligan, P.; Whetstine, J.R.; Cole, P.A.; Casero, R.A.; Shi, Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119, 941–953.
    99. Froimchuk, E.; Jang, Y.; Ge, K. Histone H3 lysine 4 methyltransferase KMT2D. Gene 2017, 627, 337–342.
    100. Hyun, K.; Jeon, J.; Park, K.; Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 2017, 49, e324.
    101. Cao, H.; Li, L.; Yang, D.; Zeng, L.; Yewei, X.; Yu, B.; Liao, G.; Chen, J. Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents. Eur. J. Med. Chem. 2019, 179, 537–546.
    102. Yin, C.; Ke, X.; Zhang, R.; Hou, J.; Dong, Z.; Wang, F.; Zhang, K.; Zhong, X.; Yang, L.; Cui, H. G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2019, 33, 14036–14050.
    103. Becker, J.S.; Nicetto, D.; Zaret, K.S. H3K9me3-Dependent Heterochromatin: Barrier to Cell Fate Changes. Trends Genet. TIG 2016, 32, 29–41.
    104. Scheer, S.; Zaph, C. The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function. Front. Immunol. 2017, 8, 429.
    105. Mayr, C.; Helm, K.; Jakab, M.; Ritter, M.; Shrestha, R.; Makaju, R.; Wagner, A.; Pichler, M.; Beyreis, M.; Staettner, S.; et al. The histone methyltransferase G9a: A new therapeutic target in biliary tract cancer. Hum. Pathol. 2018, 72, 117–126.
    106. Wei, L.; Chiu, D.K.; Tsang, F.H.; Law, C.T.; Cheng, C.L.; Au, S.L.; Lee, J.M.; Wong, C.C.; Ng, I.O.; Wong, C.M. Histone methyltransferase G9a promotes liver cancer development by epigenetic silencing of tumor suppressor gene RARRES3. J. Hepatol. 2017, 67, 758–769.
    107. Casciello, F.; Windloch, K.; Gannon, F.; Lee, J.S. Functional Role of G9a Histone Methyltransferase in Cancer. Front. Immunol. 2015, 6, 487.
    108. Chen, M.W.; Hua, K.T.; Kao, H.J.; Chi, C.C.; Wei, L.H.; Johansson, G.; Shiah, S.G.; Chen, P.S.; Jeng, Y.M.; Cheng, T.Y.; et al. H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010, 70, 7830–7840.
    109. Ding, J.; Li, T.; Wang, X.; Zhao, E.; Choi, J.H.; Yang, L.; Zha, Y.; Dong, Z.; Huang, S.; Asara, J.M.; et al. The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab. 2013, 18, 896–907.
    110. Wozniak, R.J.; Klimecki, W.T.; Lau, S.S.; Feinstein, Y.; Futscher, B.W. 5-Aza-2’-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene 2007, 26, 77–90.
    111. Hua, K.T.; Wang, M.Y.; Chen, M.W.; Wei, L.H.; Chen, C.K.; Ko, C.H.; Jeng, Y.M.; Sung, P.L.; Jan, Y.H.; Hsiao, M.; et al. The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis. Mol. Cancer 2014, 13, 189.
    112. Duvall-Noelle, N.; Karwandyar, A.; Richmond, A.; Raman, D. LASP-1: A nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex. Oncogene 2016, 35, 1122–1133.
    113. Bárcena-Varela, M.; Caruso, S.; Llerena, S.; Álvarez-Sola, G.; Uriarte, I.; Latasa, M.U.; Urtasun, R.; Rebouissou, S.; Alvarez, L.; Jimenez, M.; et al. Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma. Hepatology 2019, 69, 587–603.
    114. Cartron, P.F.; Blanquart, C.; Hervouet, E.; Gregoire, M.; Vallette, F.M. HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression. Mol. Oncol. 2013, 7, 452–463.
    115. Borutinskaitė, V.; Virkšaitė, A.; Gudelytė, G.; Navakauskienė, R. Green tea polyphenol EGCG causes anti-cancerous epigenetic modulations in acute promyelocytic leukemia cells. Leuk. Lymphoma 2018, 59, 469–478.
    116. Macaluso, M.; Cinti, C.; Russo, G.; Russo, A.; Giordano, A. pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-alpha in breast cancer. Oncogene 2003, 22, 3511–3517.
    117. Avvakumov, G.V.; Walker, J.R.; Xue, S.; Li, Y.; Duan, S.; Bronner, C.; Arrowsmith, C.H.; Dhe-Paganon, S. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 2008, 455, 822–825.
    118. Misaki, T.; Yamaguchi, L.; Sun, J.; Orii, M.; Nishiyama, A.; Nakanishi, M. The replication foci targeting sequence (RFTS) of DNMT1 functions as a potent histone H3 binding domain regulated by autoinhibition. Biochem. Biophys. Res. Commun. 2016, 470, 741–747.
    119. Nishiyama, A.; Yamaguchi, L.; Sharif, J.; Johmura, Y.; Kawamura, T.; Nakanishi, K.; Shimamura, S.; Arita, K.; Kodama, T.; Ishikawa, F.; et al. Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 2013, 502, 249–253.
    120. Qin, W.; Wolf, P.; Liu, N.; Link, S.; Smets, M.; La Mastra, F.; Forné, I.; Pichler, G.; Hörl, D.; Fellinger, K.; et al. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res. 2015, 25, 911–929.
    121. Yamaguchi, L.; Nishiyama, A.; Misaki, T.; Johmura, Y.; Ueda, J.; Arita, K.; Nagao, K.; Obuse, C.; Nakanishi, M. Usp7-dependent histone H3 deubiquitylation regulates maintenance of DNA methylation. Sci. Rep. 2017, 7, 55.
    122. Yarychkivska, O.; Tavana, O.; Gu, W.; Bestor, T.H. Independent functions of DNMT1 and USP7 at replication foci. Epigenet. Chromatin 2018, 11, 9.
    123. Du, Z.; Song, J.; Wang, Y.; Zhao, Y.; Guda, K.; Yang, S.; Kao, H.Y.; Xu, Y.; Willis, J.; Markowitz, S.D.; et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci. Signal. 2010, 3, ra80.
    124. Zhang, C.; Li, H.; Wang, Y.; Liu, W.; Zhang, Q.; Zhang, T.; Zhang, X.; Han, B.; Zhou, G. Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications. J. Hepatol. 2010, 53, 889–895.
    125. Izquierdo-Torres, E.; Hernández-Oliveras, A.; Meneses-Morales, I.; Rodríguez, G.; Fuentes-García, G.; Zarain-Herzberg, Á. Resveratrol up-regulates ATP2A3 gene expression in breast cancer cell lines through epigenetic mechanisms. Int. J. Biochem. Cell Biol. 2019, 113, 37–47.
    126. Nandakumar, V.; Vaid, M.; Katiyar, S.K. (-)-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis 2011, 32, 537–544.
    127. Majid, S.; Dar, A.A.; Ahmad, A.E.; Hirata, H.; Kawakami, K.; Shahryari, V.; Saini, S.; Tanaka, Y.; Dahiya, A.V.; Khatri, G.; et al. BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis 2009, 30, 662–670.
    128. Kondo, Y.; Shen, L.; Issa, J.P. Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol. Cell. Biol. 2003, 23, 206–215.
    129. Jiao, D.; Huan, Y.; Zheng, J.; Wei, M.; Zheng, G.; Han, D.; Wu, J.; Xi, W.; Wei, F.; Yang, A.G.; et al. UHRF1 promotes renal cell carcinoma progression through epigenetic regulation of TXNIP. Oncogene 2019, 38, 5686–5699.
    130. Beck, A.; Trippel, F.; Wagner, A.; Joppien, S.; Felle, M.; Vokuhl, C.; Schwarzmayr, T.; Strom, T.M.; von Schweinitz, D.; Längst, G.; et al. Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma. Clin. Epigenet. 2018, 10, 27.
    131. Shen, W.C.; Lai, Y.C.; Li, L.H.; Liao, K.; Lai, H.C.; Kao, S.Y.; Wang, J.; Chuong, C.M.; Hung, S.C. Methylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis. Nat. Commun. 2019, 10, 2226.
    132. Huang, Y.; Stewart, T.M.; Wu, Y.; Baylin, S.B.; Marton, L.J.; Perkins, B.; Jones, R.J.; Woster, P.M.; Casero, R.A., Jr. Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2009, 15, 7217–7228.
    133. Jin, W.; Chen, L.; Chen, Y.; Xu, S.G.; Di, G.H.; Yin, W.J.; Wu, J.; Shao, Z.M. UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer. Breast Cancer Res. Treat. 2010, 123, 359–373.
    134. Abusnina, A.; Keravis, T.; Yougbaré, I.; Bronner, C.; Lugnier, C. Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigenetic integrator UHRF1. Mol. Nutr. Food Res. 2011, 55, 1677–1689.
    135. Moseley, V.R.; Morris, J.; Knackstedt, R.W.; Wargovich, M.J. Green tea polyphenol epigallocatechin 3-gallate, contributes to the degradation of DNMT3A and HDAC3 in HCT 116 human colon cancer cells. Anticancer Res. 2013, 33, 5325–5333.
    136. Yu, C.; Xing, F.; Tang, Z.; Bronner, C.; Lu, X.; Di, J.; Zeng, S.; Liu, J. Anisomycin suppresses Jurkat T cell growth by the cell cycle-regulating proteins. Pharmacol. Rep. PR 2013, 65, 435–444.
    137. Lin, Y.; Chen, W.; Wang, Z.; Cai, P. Emodin promotes the arrest of human lymphoma Raji cell proliferation through the UHRF1‑DNMT3A‑∆Np73 pathways. Mol. Med. Rep. 2017, 16, 6544–6551.
    138. Jang, S.Y.; Hong, D.; Jeong, S.Y.; Kim, J.H. Shikonin causes apoptosis by up-regulating p73 and down-regulating ICBP90 in human cancer cells. Biochem. Biophys. Res. Commun. 2015, 465, 71–76.
    139. Krifa, M.; Leloup, L.; Ghedira, K.; Mousli, M.; Chekir-Ghedira, L. Luteolin induces apoptosis in BE colorectal cancer cells by downregulating calpain, UHRF1, and DNMT1 expressions. Nutr. Cancer 2014, 66, 1220–1227.
    140. Krifa, M.; Alhosin, M.; Muller, C.D.; Gies, J.P.; Chekir-Ghedira, L.; Ghedira, K.; Mély, Y.; Bronner, C.; Mousli, M. Limoniastrum guyonianum aqueous gall extract induces apoptosis in human cervical cancer cells involving p16 INK4A re-expression related to UHRF1 and DNMT1 down-regulation. J. Exp. Clin. Cancer Res. CR 2013, 32, 30.
    141. Jenkins, Y.; Markovtsov, V.; Lang, W.; Sharma, P.; Pearsall, D.; Warner, J.; Franci, C.; Huang, B.; Huang, J.; Yam, G.C.; et al. Critical role of the ubiquitin ligase activity of UHRF1, a nuclear RING finger protein, in tumor cell growth. Mol. Biol. Cell 2005, 16, 5621–5629.
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