HDACs in Cellular Stress Response

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This entry is adapted from the peer-reviewed paper 10.3390/ijms23158141

Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. The dependency of cancer cells on divergent pathways in response to different environmental stresses has been well established. This is through triggering various molecular mechanisms that promote genomic instability and mutations, reprogram different metabolic systems, and alter gene expression patterns to escape the growth inhibitory signals and the body’s immune system inspection. A better understanding of the underlying molecular pathways involved in the adaption of cancer cells to different stressors might open a new avenue for more efficacious strategies for cancer therapy.

HDACs cellular stress Histone Deacetylases

1. Histone Deacetylases (HDACs)

1.1. HDACs Classification

In the human genome, the HDACs superfamily consists of 18 members organized into four major classes. The classification can be based on structure, function, and subcellular localization, as well as their homology with yeast HDACs and co-factors. Classes I, II, and IV are zinc-dependent metalloproteins in which a zinc molecule is required in the active site as a cofactor. Class III HDACs are nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that require NAD+ instead of Zn²⁺ as a cofactor and have a structural homology to yeast sir2 proteins ^[1]^[2]. Class III HDACs are resistant to HDAC inhibitors (HDACIs) and their exact function in the cell cycle and carcinogenesis is currently dubious. While some have been shown to function as oncoproteins, others have been described as tumor suppressors ^[3]. Class I HDACs are highly identical to yRPD3, a yeast transcriptional regulator. This class includes HDACs 1, 2, 3, and 8 and is present most abundantly in the nucleus. Class II is related to the yeast Hda1 deacetylase enzyme, and it includes HDACs 4–7, 9, and 10. The class II HDACs determine the status of non-histone substrate acetylation, therefore the class is further subdivided into Class IIa (HDACs 4, 5, 7, and 9) that constantly travels between the cytoplasm and the nucleus and Class IIb (HDACs 6 and 10) that is localized mainly in the cytoplasm and is characterized by possessing two deacetylase domains ^[4]. Class III HDACs are comparable to yeast SIR2 and include seven members of the Sirtuins (SIRT) family. This class of HDACs has the ability to target proteins in the nucleus, cytoplasm, and mitochondria for posttranslational modifications such as acetylation or ADP ribosylation ^[5]. Finally, Class IV HDACs includes only HDAC 11, which is mainly localized in the nucleus and has a structural similarity to both class I and II, especially to HDACs 3 and 8 ^[6].

1.2. Dysregulation of HDACs in Cancer

The regulatory function of HDACs in gene transcription and protein activity make these proteins an essential player in a wide array of critical cellular signaling pathways through modulating the acetylation of histone and nonhistone substrates. As shown in Figure 1, the aberrant function of HDACs was described to either regulate the oncogenic cell signaling pathway (Figure 1A) or repress tumor suppressor gene activity (Figure 1B) ^[7]^[8]. It was reported that the aberrant expression of HDACs can affect the function of proteins involved in the cell cycle, proliferation, differentiation, angiogenesis, invasion, metastasis, and apoptosis ^[7]^[9]^[10]^[11]^[12]^[13]. The overexpression of HDACs becomes well-established in different types of cancer. This is evident with HDAC1 overexpression in prostate cancer and HDAC2 overexpression in gastric, colorectal, and endometrial sarcomas, which is correlated with decreased expression of p21 ^[14]. In addition, HDAC4 overexpression was investigated in esophageal carcinoma and was found to be significantly correlated with a higher rate of cell proliferation and tumor migration and lymph node metastasis, resulting in a higher tumor pathological grade and lower survival rate ^[15]. Moreover, Halkidou et al. reported that a high level of HDAC4 is associated with hormone-resistant cases of prostate cancer patients ^[14]^[15]. In line with this, the knockdown of HDAC4 in several cancer cell lines was found to stimulate p21 expression and consequently inhibit tumor cell proliferation in vitro and tumor growth in vivo ^[16]^[17]. In addition, studies revealed the potential role of the abnormal recruitment of HDACs to specific promoters through the interaction with fusion proteins in hematological malignancies ^[18]^[19]. Abnormal recruitment and function of HDACs can be raised from dysregulation in the expression pattern of HDACs. ^[17]^[20]^[21]. Collectively, the inhibition of critical growth suppressive genes by the upregulation of HDACs is a dominant underlying mechanism in the promotion of cancer cell development and proliferation that can be counteracted by the inhibition of HDACs.

Figure 1. HDACs as tumor promoters and suppressors. (A) HDACs are overexpressed in cancer, which promotes cellular proliferation and suppresses apoptosis and cell cycle arrest. (A1) Some HDACs (e.g., HDAC2) stabilize the beta-catenin complex, boosting cell survival and proliferation. (A2) HDACs are involved in the disruption of cell cycle checkpoints by obstructing the expression of tumor suppressor genes such as p53 and p21. (A3) Certain HDACs, such as HDAC1, reduce the transcription activity of estrogen receptor-α (ER-α), resulting in growth promotion. (A4) HDACs (e.g., HDAC6) increase the activation of MAPK through inducing the production of reactive oxygen species (ROS) via NADPH oxidase, thus promoting cell proliferation and survival. (A5) Under hypoxia, HDACs (e.g., HDAC1) stabilize HIF-1α through deacetylation, which, in turn, activates the transcription of genes involved in oxygen delivery, energy metabolism, angiogenesis, and apoptosis. (A6) The deacetylation of cell motility proteins (tubulin and cortactin) by HDACs (e.g., HDAC6) drives the progression of a primary tumor to invasion and metastasis. (A7) In hematological malignancies, PML-RAR oncofusion proteins act as altered transcription factors, which aberrantly recruit HDACs to the promoter site of retinoic acid (RA) genes, thus suppressing myeloid differentiation and causing malignant transformation. (B) Some HDACs have tumor suppressor activities and they are genetically downregulated in cancer. (B1) HDACs suppress tumor growth through activating JNK-mediated Beclin1 dissociation from Bcl-2 to induce caspase-independent autophagy death. (B2) HDACs (e.g., HDAC10) inhibit invasion and metastasis through reducing the histone acetylation level at the promoter sites of the matrix metalloproteinases (MMP2 and MMP9) genes, thereby suppressing their expression. Additionally, HDACs (e.g., HDAC2) suppress cancer metastasis through inhibiting expression of LncRNA H19, a miR-22-3P sponge that upregulates the expression of MMP14, by histone H3K27 deacetylation at its promoter site. (B3) Some HDACs (e.g., HDAC1) are involved in cell cycle regulation by forming a complex with E2F and RB that represses cell cycle progression genes. Mutations in HDAC1 reduce its recruitment and binding to E2F-regulated promoters, thereby reducing their interaction with retinoblastoma protein (Rb). This results in preventing the repression of cell cycle genes by retinoblastoma (Rb). Abbreviations: APC, adenomatous polyposis coli; TSG, tumor suppressor gene; ER, estrogen receptor; ERE, estrogen response element; ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; HIF-1α, hypoxia-inducible factor-1; HRE, hypoxia-response element; VEGF, vascular endothelial growth factor; RAR, retinoic acid receptor; PML, promyelocytic leukemia; HAT, histone acetyltransferase; JNK, c-Jun N-terminal kinases; Bcl-2, B-cell lymphoma 2; MMP, matrix metalloproteinases; miR, microRNA; Rb, retinoblastoma.

Despite the broad range of anticancer effects of HDACIs that propose an oncogenic role of HDACs in tumor development, it has been found that the genetic downregulation of HDACs might have tumorigenic effects. The overexpression of HDAC6 in breast cancer patients at mRNA and protein levels was reported to result in a better prognosis than for those with low levels in terms of survival rates ^[22]. Another study reported that the reduction in the expression of class II HDAC genes, HDACs 5 and 10, in lung cancer patients was associated with a poor prognosis in which HDAC10 was the strongest predictor of a poor prognosis ^[23]. Altogether, the dysregulated function of HDACs in cancer can contribute to either tumor promotion or suppression.

2. Role of HDACs in Cellular Stress Response

2.1. Genotoxic Stress (DNA Replication Stress, DNA Damage Response, and DNA Repair Pathways)

DNA damage is a crucial factor in the development and progression of cancer. Cancer cells undergo genotoxic stress when they encounter endogenous or exogenous DNA-damaging agents that have a direct or indirect impact on the integrity of their DNA. In the presence of DNA damage, cancer cells respond by activating biochemical repair machinery that leads to either enhancing cell survival or inducing cell death. Thus, incompetent DNA repair is a predominant driving force behind cancer establishment, progression, and evolution ^[24].

Ataxia-telangiectasia mutated (ATM) protein has a leading role in the DNA damage response. ATM stimulates the activation of the BRCA1, CHK2, and p53 genes, leading to cell cycle arrest and DNA repair through the activation of the CDKN1A (p21), GADD45A, and RRM2B genes ^[25]. Over-activation of ATM promotes the adaptation of cancer cells to genotoxic stress. Conversely, impaired ATM function exhibits chromatin exposure and augments genomic instability, which enhances sensitivity to DNA-damaging modalities (e.g., irradiation, and chemotherapeutics) ^[26]. It was demonstrated that selective depletion of HDAC1 and HDAC2 was sufficient to reduce ATM activation, thus toning down the subsequent phosphorylation of BRCA1, CHK2, and p53 and increasing the susceptibility to DNA break induction in several tumor types ^[25]. Interestingly, the silencing of HDAC4 by RNA interference downregulated the level of 53BP1 protein, a well-known tumor suppressor protein that participates in the early steps of the DNA-damage-signaling pathways, which abrogated the DNA-damage-induced G2/M checkpoint arrest and increased the radiosensitivity of HeLa cells (Figure 2A). Thus, HDAC4 was proposed to have a prominent role in cell cycle regulation after ionizing radiation ^[27]. Furthermore, yeast SIR3 has been shown to be prominently recruited at various sites of DNA damage. The accumulation of this type of deacetylase has been hypothesized to facilitate DNA repair and to protect the unrepaired DNA ends through induction of compact chromatin alignment ^[28]. In a similar manner, SIRT1 has been identified as a major player in the DNA damage response, acting as a deacetylase of proteins involved in DNA repair at sites of DNA damage ^[29]. Moreover, SIRT1 functions as an enhancer of DNMT1, DNMT3B, and zeste homologue 2 (EZH2). These proteins are recruited at sites of DNA double strand breaks and induce histone repressive modifications such as hypoacetylation of H4K16, H3K9me2/me3, and H3K27me3. These histone modifications help in the establishment of the compact chromatin around the damaged site by forming a silencing complex with DNMT3b, polycomb, and a repressive complex of four components (SIRT1 and EZH2) that pairs with γH2AX, forming DNA-damage-induced foci (Figure 2A) ^[30]. In addition to H4K16 deacetylation, SIRT1 was reported to deacetylate a member of the HAT family called hMOF (human MOF), which consequently affected its recruitment at sites of DNA damage and caused downregulation of DNA double strand break repair genes such as BRCA2, RAD50, and FANCA in human colorectal cancer cells (HCT116) ^[31]. On the other side, SIRT1, along with E2F1 transcription factor, are stimulated among the signaling cascade initiated by DNA single strand break molecular sensor PARP1 to guide the transcription of ADP-ribosylation factor (ARF), which is one of the crucial genes that are modulated in response to continuous DNA breaks (Figure 2B) ^[32]^[33].

Figure 2. Role of HDACs in the modulation of DNA repair machinery. (A) After DNA double strand breakage, (A1) SIRT1 is directed towards the DNA damage site to induce chromatin reorganization by recruiting epigenetic machinery including DNMT1, DNMT3B, and EZH2. These epigenetic modifiers induce histone repressive modifications, such as hypoacetylation of H4K16 and methylation of H3K9 and H3K27, that help to establish the compaction of chromatin around the damaged site. (A2) HDAC1 and HDAC2 contribute to ATM activation in several tumor types, thereby enhancing the subsequent phosphorylation of BRCA1, CHK2, and p53, which decreases the susceptibility of DNA breakage. (A3) HDAC4 increases the expression of the tumor suppressor gene 53BP1, a protein involved in the early stages of DNA damage signaling. This signaling cascade facilitates the phosphorylation and activation of p53 protein, which promotes cell cycle arrest to allow DNA repair and/or apoptosis. (B) Upon induction of single stand breaks, poly(ADP-ribose) synthesis is catalyzed by PARP1 at unrepaired single break sites, which reduces the activity of NAD+-dependent deacetylase SIRT1 through decreasing the cellular concentration of NAD+. Consequently, the acetylation of E2F1 is maintained, which activates the transcription of ARF, which inhibits MDM2, a negative regulator of p53. This allows p53 to exert its tumor suppressor transcriptional regulation or/and to induce apoptosis. Abbreviations: DNMT, DNA methyltransferase 1; DNMT3B, DNA methyltransferase 3B; EZH2, enhancer of zeste homolog 2; ATM, ataxia-telangiectasia mutated; BRCA1, breast cancer gene 1; CHK2, checkpoint kinase 2; 53BP1, p53-binding protein 1; ATR, ataxia-telangiectasia and Rad3-related; ATRIP, ATR interacting protein; PARP1, poly(ADP-ribose) polymerase 1; NAD+, nicotinamide adenine dinucleotide; E2F1, E2F transcription factor 1; ARF, alternative reading frame; MDM2, mouse double minute 2.

In addition to the significant role of HDACs in the DNA damage response, they participate in the regulation of replication and S-phase progression. It was suggested that HDACs operate the progression of the replication fork by inducing global changes in chromatin structure that affect the functions of DNA polymerase. Dysregulation of the chromatin structure results in uncontrolled origin firing and replication fork collapse, which promotes DNA damage and genomic instability, leading to cell death ^[34]^[35]. Previously, it was demonstrated that treatment of cutaneous T cell lymphoma (CTCL) cell lines (HH and Hut78) with a selective HDAC3 inhibitor caused a 50% reduction in DNA replication fork velocity and remarkable cell growth arrest ^[36]. These results were consistent with another study conducted by Srividya et al., which showed that genetic deletion of HDAC3 in mouse embryonic fibroblasts (MEFs) triggered apoptosis and yielded very early embryonic lethality. They attributed these effects to inefficient removal of acetyl residues from the histones, which causes a flaw in chromatin assembly accompanied with persistent DNA damage accumulation that usually occurs during DNA replication and impairs the progression to the G2 phase ^[37]. The critical role of HDACs in the adaptation to genotoxic stress supports the potential approach of targeting them in rapidly proliferating tumor cells while being nondestructive to the surrounding nonmalignant cells.

2.2. Proteotoxic Stress (Heat Shock Response and Endoplasmic Reticulum Stress)

Dysregulated protein homeostasis is one of the emerging processes involved in tumor progression. The rate of protein formation is influenced by transcription, translation, and degradation processes; all of them are regulated by the chromatin arrangement state. Dysregulation in proteostasis results in impaired protein synthesis or misfolded proteins. This triggers endoplasmic reticulum (ER) stress, which could result in an overall degeneration in cellular function ^[38]^[39]^[40]. The ER is the main area for monitoring protein products, where only the correctly posttranslational folded proteins can exit the ER to the Golgi apparatus to be delivered to their distinct destination. Interestingly, a group of proteins called chaperones exist in the ER and cytosol to maintain protein homeostasis by programming the folding of newly synthesized proteins and partially folded proteins and prevents the misfolded protein aggregates ^[41]. In the tumor microenvironment, hypoxia and nutrient deprivation states induce ER stress. Therefore, cancer cells depend on an interconnected network of proteostasis signaling pathways, such as the unfolded protein response (UPR), to sustain protein stability. The UPR pathway modulates the rate of protein synthesis mainly through interacting with proteasomal systems such as the macroautophagic (autophagy-lysosome) system, aggresomal pathway and heat shock chaperone protein system, to correct impaired protein clearance and folding or to induce apoptosis in persistent ER stress ^[42].

Cytoplasmic HDAC6 was found to represent a master chief in the regulation of the cytoprotective response to proteotoxic stress through association with proteasomal proteins (Figure 3). For instance, HDAC6 forms a complex with p97/VCP and UFD3/PLAP, which are involved in controlling the ubiquitin/proteasome system. P97/VCP is a chaperone that facilitates the degradation of misfolded proteins when the ubiquitin-dependent proteasomal turnover of proteins is overwhelmed and paralyzed (Figure 3A) ^[43]^[44]. In addition, HDAC6 induces the expression of dominant chaperons in response to the accumulation of ubiquitinated protein aggregates. Initially, HDAC6 senses the abnormal accumulation of ubiquitinated misfolded proteins via its ubiquitin-binding activity. Consequently, it promotes the dissociation of a repressive HDAC6/heat-shock factor 1 (HSF1)/heat-shock protein 90 (HSP90) complex, where the liberated HSF1 activates HSP gene expression to induce cell survival (Figure 3B) ^[9]^[45]^[46]. Accordingly, HDAC6 inhibition has been shown to increase the acetylation of HSP90 and suppress its function as a molecular chaperon, which increases the number of misfolded proteins in the cell (Figure 3C). When the rate of misfolded proteins exceeds the processing or folding capacity of protein chaperones, it will result in chronic unresolved ER stress and subsequent apoptosis induction in cancer cells ^[9]. In addition to HSP90, HDACIs increased the acetylation levels of other chaperones such as regulated protein 78 (GRP78), which causes the induction of protein misfolding and proteotoxic stress, leading to the suppression of cellular proliferation and subsequent apoptosis. On the other hand, HDACIs can induce ER stress in cancer cells indirectly through the upregulation of the reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene, which is a well-known member of the metastasis suppressor genes that was found to modulate tumor cell invasiveness and metastasis. The upregulation of RECK was found to sequester GRP78, which releases ER transmembrane sensor proteins to eventually induce ER stress and activate apoptosis ^[41]^[47]^[48]^[49]^[50]. Collectively, these studies present a new HDAC-targeted approach in limiting metastasis and angiogenesis and in increasing the susceptibility of cancer cells to ER stress through induction of the intracellular proteotoxic environment ^[51].

Figure 3. HDAC6 regulates the response to misfolded protein aggregates. Under proteotoxic stress, cancer cells evolve an intricate set of signaling to allow the cell to respond to the presence of misfolded proteins within the endoplasmic reticulum (ER). HDAC6 is considered a master regulator in misfolded protein processing through three different pathways: (A) HDAC6 forms a complex through its ZnF-UBP domain with proteasomal proteins such as p97/VCP that binds to polyubiquitinated proteins, facilitating their proteasomal degradation; (B) In unstressed cells, HDAC6 usually exists in complex with an inactive HSF1 and HSP90. Upon ER stress, this complex is dissociated and the liberated HSF1 activates the expression of heat shock genes (HSP70 and HSP27). These heat shock proteins are essential components of the cell machinery that are required for the proper folding of proteins and the degradation of damaged proteins to protect against the adverse effects of proteotoxic stress; and (C) HDAC6 deacetylates HSP90, enhancing its chaperone activity, and facilitates the recruitment of other chaperones to reduce the level of unfolded proteins. At the end, upgrading the chaperone capacity in processing misfolded proteins by HDAC6 promotes cell survival. Abbreviations: Ub, ubiquitin; VCP, valosin-containing protein; HSF1, heat shock transcription factor 1; HSP90, heat shock protein 90; HSP70, heat shock protein 70; HSP27, heat shock protein 27.

2.3. Oxidative Stress

Reactive oxygen species (ROS) are byproducts of the normal oxygen metabolism, which serve a critical role in several biological functions, signaling pathways and redox homeostasis. However, the strict regulation of ROS by scavenging systems is compulsory because of their possible toxic impact on cellular structures. Indeed, the impairment that ROS can impose on the cell does not solely depend on their intracellular levels, but also on the equilibrium between ROS and the endogenous antioxidant species. When such an equilibrium is disturbed, oxidative stress is provoked, resulting in severe damage to intracellular biological components such as DNA, RNA, and proteins, which is a recognized hallmark of cancer.

Cancer cells usually exist in a hypoxic microenvironment, which further boosts their metabolic activity and oncogenic stimulation that in turn generates a high level of ROS ^[52]. Strikingly, cancer cells use several mechanisms, such as activation of ROS-scavenging systems, suppression of cell death factors, and generation of lactate instead of employing aerobic respiration, to adapt to the massive ROS accumulation without disturbing the energy demand of cancer cells to support their proliferation and survival ^[53]^[54]^[55]. There are many antioxidant genes that are associated with cellular responses to oxidative stress including superoxide dismutases (SODs), glutathione peroxidases (GPXs), glucocorticoid receptors, heme oxygenase (HMOXs), and hypoxia-inducible factor-1α (HIF-1 α). Many of these genes have been reported to be regulated by epigenetic mechanisms. One of the most powerful and well-known examples of cellular defense machinery against oxidative damage is the KEAP1-NRF2 pathway, which includes the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative cytoplasmic regulator kelch-like ECH-associated protein 1 (Keap1). Under oxidative and electrophilic stress, Keap1 allows Nrf2 phosphorylation and translocation into the nucleus. In the nucleus, Nrf2 activates the expression of a wide range of antioxidative detoxifying enzymes by binding to the antioxidant response element (ARE) in their regulatory regions that rescues the cell from oxidative injury ^[56]. Surprisingly, HDACs regulate Nrf2 activity and ARE-dependent gene expression through the direct modulation of Nrf2 acetylation. This was evident by the increased acetylation level of Nrf2 by selective inhibitors of Sirtuin 1 (SIRT1), such as EX-527 and nicotinamide, which results in enhancing the binding of Nrf2 to ARE and thereby stimulating Nrf2-mediated gene expression. In the same line, SIRT1 activators (such as resveratrol), have been shown to deacetylate Nrf2 and to suppress Nrf2 signaling (Figure 4A) ^[57]. In addition, HDACs and their inhibitors were reported to regulate the Nrf2 pathway via the adjustment of histone acetylation at the promoter regions of antioxident genes. Liu et al. reported that HDAC3 is a negative regulator of the Nrf2 pathway through the function of the p65 subunit of NF-κB, which enhances the interaction of HDAC3 with MafK, a known dimerization partner with Nrf2. This interaction causes the recruitment of HDAC3 to ARE that consequently promotes the maintenance of the histone hypoacetylation state and hence represses ARE-dependent gene expression (Figure 4B) ^[58]. HDAC1 was reported to work as a corepressor of the transcription factor basic leucine zipper transcription factor 1 (Bach1), which has an important role in repressing the oxidative stress response through forming a complex with p53 and HDAC1 and the nuclear corepressor N-CoR, inhibiting cellular senescence of murine embryonic fibroblasts in response to oxidative stress (Figure 4C) ^[52]^[59].

Figure 4. HDACs coordinate the cellular response to oxidative stress. HDACs coordinate the cellular response to oxidative stress. As a defense mechanism against oxidative stressors, Nrf2 acts as a redox-sensitive transcription factor. Under homeostatic conditions, Keap1 sequesters Nrf2 in the cytoplasm, resulting in its degradation by proteasome. When the cells are subjected to oxidative stress, Nrf2 is activated through its dissociation from the Keap1 complex. Then, the Nrf2 protein is transported to the nucleus, where it is acetylated and dimerized with the MAF protein at the antioxidant reactive element (ARE) site in the promoters of antioxidant genes. Through this process, antioxidant genes are activated to scavenge excess reactive oxygen species (ROS) and maintain mitochondrial function. In response to oxidative stress, HDACs act as a negative regulator of the Nrf2 pathway. (A) SIRT1 inhibits Nrf2 acetylation, which reduces its binding to ARE and thereby obstructs Nrf2-mediated gene expression. (B) HDAC3 is recruited to the ARE site and induces a histone hypoacetylation state, hence repressing ARE-dependent gene expression. (C) HDAC1 forms a complex with Bach1, which competes with Nrf2 for the binding to transcription cofactor MAF in oxidative-stress-response genes. Bach1 acts as a functional inhibitor of Nrf2 by forming a complex with nuclear co-repressor NCoR. Abbreviations: Nrf2, NF-E2–related factor 2; Keap1, Kelch-like ECH associated protein 1; ROS, reactive oxygen species; MAF, musculoaponeurotic fibrosarcoma; ARE, antioxidant responsive element; Bach1, BTB domain and CNC homolog 1; NCoR, nuclear receptor corepressor 1.

Additionally, the functional role of HDACs in regulating oxidative stress response was demonstrated through HIF-1. HIF-1 is one of the dominant modulators of genes responsive to hypoxia, a common event in solid tumors, that causes an excessive production of ROS, leading to oxidative stress. HIF-1 is composed of two subunits: the hypoxia-regulated HIF-1α and the oxygen-insensitive HIF1ß subunits, which form a heterodimer and bind to hypoxia responsive elements (HREs) in oxygen-regulated genes including VEGF. These genes are involved in cellular biological processes such as angiogenesis and augment oxygen delivery to tumor hypoxic regions. In both human and mouse cell lines, it was reported that class I HDACs, in particular HDAC1 and HDAC3, directly interact with the HIF-1α protein and induce its deacetylation, which enhances its stability and transactivation function under hypoxic conditions. These results actively indicate that the stabilization of HIF-1α protein is accelerated through direct interaction with HDAC1 and HDAC3, leading to enhanced tumor angiogenesis ^[60]. Similarly, a positive crosstalk was established between HDAC1, HIF-1α, and metastasis-associated protein 1 (MTA1) in which HDAC1 participates in the MTA1-induced stabilization of HIF-1α. It was suggested that hypoxia induces the expression of MTA1, which inhibits the acetylation of HIF-1α by recruiting HDAC1, resulting in the stabilization of HIF-1α and inhibiting its degradation. These findings were further confirmed using the potent HDACs inhibitor Trichostatin A (TSA), which reduced the stability of HIF-1α in breast cancer cell lines. This establishes a close connection between MTA1-associated metastasis and HIF-1-induced tumor angiogenesis through the activity of HDAC1 ^[61]. In addition to HDAC1 and HDAC3, HDAC7 was reported to be co-translocated with HIF-1α to the nucleus under hypoxic conditions, where it subsequently increases the transcriptional activity of HIF-1α through the formation of a complex composed of HIF-1α, HDAC7, and p300 ^[62]. However, the underlying mechanism of transcriptional regulation of HIF-1α by HDAC7 is still not fully understood.

For NAD-dependent deacetylases, SIRT1 was reported to modulate different angiogenesis-related genes under oxidative stress, such as membrane-anchored matrix metalloproteinase MMP14 (MT1-MMP), Flt1, CXCR4, Pdgf, and EphB2 ^[63]^[64], while SIRT3 loss was associated with an increase in the production of ROS, causing the stabilization of HIF1α. Similarly, in human breast cancer, the reduction in the expression of SIRT3 results in upregulation of the HIF-1α target genes. These findings highlight the role of SIRT3 in the hypoxic response of tumor cells, exposing a potential area for therapeutic intervention ^[65]^[66]. To sum up, HDACs have ab influential role in many oxidative stress pathways, including both sensing and coordinating the cellular response to oxidative stress pathways, and HDACIs might be certified candidates for targeting oxidative stress pathways.

2.4. Metabolic Stress (Hypoglycemia and Hypoxia)

Metabolic stress is a common phenomenon in human tumors. It results from insufficient nutrient supply to tumors, which is caused by angiogenesis deficiency and elevated metabolic demands due to aggressive, uncontrolled cellular proliferation. While normal tissues have restricted cell division that is strictly regulated by growth factors and nutrient availability, tumor cells lack this control of cell division. Nevertheless, they proliferate independently of restricted nutrient supply by relying on the incompetent glycolysis process as an energy supply source, which further exaggerates their metabolic stress status ^[67]. Under normal conditions, these stressful factors drive the normal cells to metabolic catastrophe, leading to the termination of cell proliferation and growth. On the other hand, cancer cells acquire some genomic and metabolic phenotypes that help them to grow and escape the apoptotic pathways stimulated as a result of modifications in the tumor microenvironment ^[68]. The most dominant metabolic phenotype of cancer cells, which is an essential step in the adaptation to metabolic stress, is the elevation of glucose uptake and the production of lactate for aerobic glycolysis regardless of oxygen presence ^[69]. Additionally, alternative carbon and energy sources, such as fatty acids and amino acids, are used by cancer cells to fulfil increased energy demands and to respond to the various metabolic stresses and oncogenic signaling ^[70]^[71].

Protein acetylation levels were reported to be affected by cellular metabolism through the regulation of NAD+ and acetyl-CoA concentrations. Thus, HDACs have a pronounced role in the metabolic reprogramming in cancer cells ^[72]. Indeed, several reports uncovered the role of the SIRT family in manipulating several metabolic pathways. For instance, SIRT3 and SIRT6 suppress tumorigenesis by inhibiting aerobic glycolysis or a glycolytic switch (Warburg effect) through the destabilization of HIF-1α and inhibition of glycolytic kinases ^[66]. SIRT6 was also found to inhibit gluconeogenesis, which generates glucose from noncarbohydrate precursors, through the deacetylation of the transcription factor FoxO1, leading to its export to the cytoplasm. The nuclear exclusion of FoxO1 reduces the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which are rate-limiting enzymes in gluconeogenesis ^[73]. Furthermore, SIRT6 was shown to induce the deacetylation of pyruvate kinase M2 (PKM2), a glycolytic enzyme, which results in its nuclear export through exportin 4 ^[74]. Interestingly, PKM2 was found to have HDAC3-dependent regulation of the expression of oncogenes such as c-Myc and cyclin D, which promotes tumorigenesis ^[75].

Despite the negative regulation of glycolysis by SIRT6, SIRT3 and SIRT5 were found to contribute to cancer cell proliferation and survival in diffuse large B cell lymphoma and breast cancer by regulating the function of metabolic enzymes ^[76]^[77]. The depletion of SIRT3 in large B cell lymphoma blocks glutamine flux to the tricarboxylic acid (TCA) cycle through inhibition of glutamate dehydrogenase that results in the reduction of acetyl-CoA pools, which causes the induction of autophagy in cancer cells ^[77]. Similarly, the overexpression of SIRT5 in breast cancer protects the mitochondrial enzyme glutaminase (GLS) from ubiquitin-mediated degradation through SIRT5 dependent-desuccinylation of lysine164 residue, which stabilizes GLS ^[76]. Indeed, SIRT5-dependent GLS stabilization is the main mechanism by which SIRT5 promotes cancer cell growth and survival. The involvement of SIRT2 in supporting tumorigenesis through modulating metabolic pathways was also reported. SIRT2 regulates cellular metabolism and metastasis in colorectal cancer through deacetylation of isocitrate dehydrogenase 1 (IDH1), which plays an important role in glutamine metabolism. The increased deacetylation level of IDH1 at lysine 224 simulates its enzymatic activity and subsequently induces the generation of NADPH and glutathione (GSH), which protects cancer cells from ROS produced during their rapid proliferation rate. In addition, IDH1 stimulation by deacetylation induces the proteasomal degradation of HIF-1α, which exerts a suppressive effect in colorectal cancer metastasis ^[78].

HDACs were found to be involved in regulating the covalent attachment of fatty acids to proteins, which is known as fatty acylation of proteins. This protein modification is known to be essential in membrane synthesis and cellular signaling during cancer growth and progression. Surprisingly, some HDACs established a greater catalytic activity towards acyl groups when compared with acetyl peptides ^[79]^[80]. For instance, the catalytic efficiency of HDAC11 as a lysine defatty-acylase was reported to be more than 10,000-fold higher than its deacetylase activity ^[79]. Recently, SHMT2α, a mitochondrial enzyme involved in one carbon metabolism and found to exert a critical metabolic function in cancer cells, has been identified as a substrate of the lysine defatty-acylase activity of HDAC11. It was demonstrated that HDAC11 removes the acyl groups from the SHMT2α surface, which prevents its translocation to late-lysosome/endosome. This effect leads to the polyubiquitylation and degradation of type I interferon receptor chain 1 (IFNαR1), which downregulates the IFN signaling that is involved in metabolic reprogramming ^[81]. Consequently, elevenostat, which is an HDAC 11 inhibitor, represents a potential treatment approach that targets metabolic lipid dysfunction in cancer ^[82]. Overall, HDACs exert a critical role in regulating glucose homeostasis and energy balance and strengthening the metabolic phenotype of cancer cells to promote their survival regardless of the intracellular nutrient stress environment.

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