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Epigenetics and Non-Coding RNAs in Multiple Myeloma
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Multiple myeloma (MM) accounts for about 10% of hematological malignancies. It is a plasma cell malignancy that originates from the post-germinal lymphoid B-cell lineage, and is characterized by an uncontrolled clonal growth of plasma cells. The discovery of non-coding RNAs as key actors in multiple myeloma has broadened the molecular landscape of this disease, together with classical epigenetic factors such as methylation and acetylation. microRNAs and long non-coding RNAs comprise the majority of the described non-coding RNAs dysregulated in multiple myeloma, while circular RNAs are recently emerging as promising molecular targets. 

CRISPR-Cas long non-coding RNA microRNA multiple myeloma non-coding RNA
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Update Date: 31 May 2022
Table of Contents

    1. Introduction

    Multiple myeloma (MM) accounts for about 10% of hematological malignancies. It is a plasma cell malignancy that originates from the post-germinal lymphoid B-cell lineage, and is characterized by an uncontrolled clonal growth of plasma cells. It is preceded by monoclonal gammopathy of undetermined significance (MGUS) that progresses to smoldering myeloma and finally to symptomatic MM [1].
    Frequently, these clones of plasma cells invade the adjacent bone and occasionally infiltrate multiple organs, causing symptoms such as hypercalcemia, renal insufficiency, anemia, and bone lesions. In the past decades, the therapeutic landscape of MM has improved with the development of targeted therapies, chemotherapeutic agents, and immunotherapy. Despite this, relapses are common [2].

    2. Methylation

    DNA methylation is a central epigenetic modification in cancer. It plays an important regulatory role in transcription, chromatin structure and genomic stability, X chromosome inactivation, genomic imprinting, and carcinogenesis [3]. Global hypomethylation in cancer cells was one of the first epigenetic alterations found in carcinogenesis. Moreover, certain genes are inactivated due to hypermethylation of CpG islands in regulatory regions. This process is catalyzed by DNA methyltransferases (DNMT) and involves the addition of a methyl group to the carbon 5 position of the cytosine ring in the CpG dinucleotide, generating a 5-methylcytosine (5mC) [4]. The opposite process of demethylation is mainly catalyzed by TET enzymes, which can oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). These oxidized products can then be removed by base excision repair and substituted by cytosine in a locus-specific manner [5]. However, despite the finding of TET2 loss-of-function mutations in some hematological malignancies, there is very few knowledge about their role in MM [6].
    Methylation patterns have been shown to be different depending on the stage of MM progression. In non-malignant stages and MGUS, demethylation occurs mainly in CpG islands. At the transition from MGUS to MM, the key feature is a strong loss of methylation, associated with genome instability. In malignant stages, changes in methylation are widespread in the genome, outside of CpG islands, and affect various pathways, such as cell cycle and transcriptional activity regulators [7]. DNMT3A is hypermethylated and underexpressed in MM, leading to a global hypomethylation. Interestingly, DNA hypermethylation in B-cell specific enhancers seems to be a key feature of MM-staged cells. These hypermethylated regions are located in binding sites of B-cell specific transcription factors, thus leading to an impaired expression of those and, consequently, a more non-differentiated cell profile in MM cells. This hypermethylation in B-cell-specific enhancers has been found in stem cells; it is progressively eliminated in non-malignant B cells and reacquired again in MM cells [8].
    Genomic studies have been performed to explain the role of promoter hypermethylation of tumor suppressor genes. Preliminary studies revealed that in MM patients, there was aberrant methylation in genes such as SOCS-1, p16, CDH1, DAPK1, and p73. Hypermethylation of crucial tumor modulating genes, such as GPX3, RBP1, SPARC, and TGFBI has been associated with a significantly shorter overall survival, independently of age, International Staging System (ISS) score, and adverse cytogenetics [9][10].
    Moreover, several signaling pathways were found to be dysregulated in MM. STAT3 overexpression due to promoter hypermethylation was associated with an adverse prognosis and was mainly induced by IL-6 signaling [11]. DNA methyltransferase inhibitors (DNMTi), such as 5-azacytidine, were shown to revert hypermethylation and exerted synergistic anti-MM effects with bortezomib [12]. Therefore, several clinical trials have been conducted to assess DNMTi efficacy in combination with anti-MM agents, such as lenalidomide or dexamethasone [13].

    3. Acetylation

    Acetylation is one of the major reversible post-translational modifications that introduces an acetyl group on histone lysine residues, thus modifying the gene expression pattern. It involves a dynamic process, consisting of a balance between the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). This balance serves as a key regulator that influences many cellular processes such as cell cycle, chromatin structure, and gene expression [4].
    HATs catalyze the attachment of acetyl groups, resulting in a less condensed chromatin structure. CREB-binding protein CBP/p300 family is a HAT type A enzyme, whose mutations are often related to cancer development. It is located in the nucleus and involved in the acetylation of histones. CBP/p300 is dysregulated in hematological malignancies [14] and, in the case of MM, inhibition of CBP/p300 has been shown to induce cell death via the reduction of IRF4 expression [15]. This could open a promising therapeutic strategy but however, the majority of studies are focused on HDACs, which catalyze the amide hydrolysis of acetylated lysines. HDACs constitute a family of 18 proteins subdivided into four classes based on homology to yeast HDACs: class I (HDAC1-3, HDAC8), class IIa (HDAC4-5, HDAC7, HDAC9), class IIb (HDAC6, HDAC10), class III (SIRT1-7), and class IV (HDAC11). Alterations in their activity have been discovered in a broad range of tumors, including MM. Their targets include histones but also non-histone proteins such as p53, Hsp90, and p65 NF-κB [16].
    The essential role played by HDACs in cancer and MM progression has led to the development of HDAC inhibition strategies. Pan-HDAC inhibitors seem to show stronger clinical inhibition of HDAC1, HDAC2, HDAC3, and HDAC6 than other HDACs. This suggests that their anti-tumor activity may focus on class I and class IIb HDAC inhibition [17]. Several HDAC inhibitors, such as romidespin (class I HDAC inhibitor) or panobinostat (pan-HDAC inhibitor) induce high cytotoxicity against MM cells, especially in combination with proteasome inhibitors such as bortezomib. Nevertheless, due to the wide range of targets, they also showed unfavorable side effects in clinical trials [18]. To avoid these problems, the development of selective HDAC inhibitors has become critical in MM research. To date, HDAC6 inhibitors (i.e., ricolinostat) are the ones showing encouraging results in MM treatment. HDAC6 is essential for aggresome formation, an alternative clearance pathway that is activated in response to proteasome inhibition to eliminate misfolded proteins [18]. The synergistic inhibition of proteasome and aggresome pathways leads to the accumulation of misfolded proteins, resulting in cell death [19], therefore, unveiling a promising strategy involving the combination of HDAC6 and proteasome inhibitors to tackle resistance in MM.

    4. Non-Coding RNAs

    Efforts in the study of the genome have classically focused on protein-coding genes that include only a small percentage of the mammalian genome. In the last years, a special emphasis has been placed on the non-protein-coding genome. The development of genomic and transcriptomic technologies has highlighted that 70% of the transcribed human genome corresponds to ncRNAs [20]. ncRNAs are divided in two groups: structural and regulatory ncRNAs. Structural ncRNAs include transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs). These ncRNAs are part of the machinery involved in protein synthesis. Regulatory ncRNAs are divided depending on their size: microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) are less than 200 nucleotides long, while long non-coding RNAs (lncRNAs) comprise the biggest. Another type of ncRNAs are circular RNAs (circRNAs), which mainly function as miRNA sponges [21].

    4.1. microRNAs

    miRNAs are 19 to 25 base-pair-long ncRNA molecules that trigger the translational repression, and sometimes degradation, of target messenger RNAs (mRNAs) with complementary sequences. Alterations in miRNAs have raised special interest in cancer research, including MM (Table 1). miRNAs constitute one of the central and most-studied post-transcriptional regulator components affecting myelomagenesis, MM progression, development, and prognosis. miRNAs can be classified into tumor-suppressive miRNAs, when they target an oncogenic gene, or oncogenic miRNAs, when they target a tumor suppressor gene, and they are tissue-specific.

    Activity/Pathway Affected

    miRNA

    Status 1

    Target

    References

    Enhances PI3K/Akt

    pathway

    miR-20a

    Cancers 14 02348 i001

    EGR2, PTEN

    [22][23]

    miR-21

    Cancers 14 02348 i001

    PIAS3

    [24]

    miR-25-3p

    Cancers 14 02348 i001

    PTEN

    [25]

    miR-221/222

    Cancers 14 02348 i001

    PUMA, PTEN, CDKN1B, p27

    [26]

    miR-410

    Cancers 14 02348 i001

    KLF10

    [27]

    Enhances mTOR pathway

    miR-19b

    Cancers 14 02348 i001

    TSC1

    [28][29]

    miR-135b, miR-642a

    Cancers 14 02348 i001

    DEPTOR

    [30]

    Related to a hypoxia

    phenotype

    miR-210

    Cancers 14 02348 i001

    DIMT1

    [31][32]

    miR-1305

    Cancers 14 02348 i001

    MDM2, IGF1, FGF2

    [33]

    Disrupts PRC2 activity

    miR-124

    Cancers 14 02348 i001

    EZH2

    [34]

    Modulates microenvironment

    miR-146a

    Cancers 14 02348 i001

    Not described

    [35]

    miR-155

    Cancers 14 02348 i001

    Not described

    [36]

    Promotes proliferation, circulating miRNAs

    miR-17-92

    Cancers 14 02348 i001

    BIM

    [28]

    miR-221/222

    Cancers 14 02348 i001

    [26]

    Circulating miRNA

    miR-1

    Cancers 14 02348 i001

    Not described

    [37]

    miR-133a/b

    Cancers 14 02348 i001

    Not described

    [37]

    miR-135b

    Cancers 14 02348 i001

    HIF1A

    [38][39]

    miR-146b

    Cancers 14 02348 i001

    Not described

    [40]

    miR-181a

    Cancers 14 02348 i001

    BCL2L11

    [41][42]

    miR-214

    Cancers 14 02348 i002

    CD276

    [43]

    Represses JAK/STAT pathway

    miR-125b

    Cancers 14 02348 i002

    IL6R, STAT3, MALAT1

    [44][45]

    miR-331-3p

    Cancers 14 02348 i002

    IL6R

    [46]

    miR-375

    Cancers 14 02348 i002

    PDPK1

    [47]

    miR-451

    Cancers 14 02348 i002

    IL6R

    [48]

    let-7b-5p

    Cancers 14 02348 i002

    IGF1R

    [49]

    Regulates cyclin activity

    miR-26a

    Cancers 14 02348 i002

    CDK6

    [50]

    miR-28-5p

    Cancers 14 02348 i002

    CCND1

    [51]

    miR-30a-3p

    Cancers 14 02348 i002

    MAF

    [52]

    miR-338-3p

    Cancers 14 02348 i002

    CDK4

    [53]

    miR-340-5p

    Cancers 14 02348 i002

    CCND1, NRAS

    [54]

    miR-196a/b

    Cancers 14 02348 i002

    CCND2

    [37]

    Regulates proliferation

    miR-22

    Cancers 14 02348 i002

    c-Myc

    [55]

    miR-29a

    Cancers 14 02348 i002

    c-Myc

    [56]

    miR-34a

    Cancers 14 02348 i002

    BCL2, CDK6, NOTCH1, c-Myc, MET, IL6R

    [45][57][58]

    miR-193a

    Cancers 14 02348 i002

    MCL1

    [59]

    miR-497

    Cancers 14 02348 i002

    BCL2

    [60]

    miR-767-5p

    Cancers 14 02348 i002

    MAPK4

    [61]

    miR-874-3p

    Cancers 14 02348 i002

    HDAC1

    [62]

    miR-1180

    Cancers 14 02348 i002

    YAP

    [63]

    Prevents angiogenesis

    miR-15a/16

    Cancers 14 02348 i002

    BCL2, VEGF, IL17

    [64]

    Regulates acetylation

    miR-29b

    Cancers 14 02348 i002

    HDAC4, MCL1

    [65]

    Regulates transcriptional activity

    miR-509-5p

    Cancers 14 02348 i002

    FOXP1

    [66]

    miR-1271-5p

    Cancers 14 02348 i002

    SOX13, HGF

    [67][68]

    Prevents hypoxia phenotype

    miR-199a-5p

    Cancers 14 02348 i002

    HIF1A, VEGFA

    [69]

    Prevents osteolytic activity

    miR-342

    Cancers 14 02348 i002

    RUNX2

    [70]

    miR-363

    Cancers 14 02348 i002

    RUNX2

    [70]

    1 Arrow up indicates overexpression of the miRNA, and arrow down indicates underexpression of the miRNA.

    miRNAs may act in clusters, where a group of miRNAs have their expression regulated concomitantly. One of the largest clusters involved in MM is miR-17-92, a six-member polycistronic cluster encoding for six individual miRNAs: miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a. Some of these miRNAs are known for regulating the PTEN/PI3K/Akt pathway (Figure 1). This cluster was demonstrated to take part in controlling cell proliferation, differentiation, and apoptosis, as it was positively regulated by c-Myc, which conferred to this cluster a key role in MM tumorigenesis [28]. Several studies have empirically proven, using functional assays, that BIM is the direct target of miR-17-92. This was confirmed in MM cells with upregulated miR-17-92 that showed an increased expression of anti-apoptotic Bcl-2 [28][71]. Despite their coordinated role, some of the miRNAs belonging to this cluster also had specific functions. Interestingly, miR-20a was highly expressed in bone marrow samples of MM patients when compared to healthy donors. The introduction of a synthetic substitutive miR-20a (mimic-based approach) showed an increased growth rate and decreased apoptosis in the U266 MM cell line, and a promoted tumor growth in a SCID/NOD mouse xenograft model [22]. PTEN was shown to be a downstream target of miR-20a, pointing out the PTEN/PI3K/Akt pathway as altered by miR-20a [23]. miR-19b specifically targeted the tumor-suppressive co-chaperone TSC1 and activated the mTOR pathway, which promoted cancer stem cell (CSC) proliferation [29].
    Figure 1. Overview of the main signaling pathways altered by miRNAs in MM cells. Oncogenic miRNAs (red) are overexpressed, and tumor-suppressive miRNAs (green) are underexpressed in MM cells.

    4.2. Long Non-Coding RNAs

    lncRNAs include ncRNAs whose transcripts are longer than 200 nucleotides. Their classification is performed depending on their localization (Figure 2). Nowadays, there is an incomplete understanding of the mechanism of action of lncRNAs, but it is widely accepted that they play an important role in cancer [20].
    Figure 2. lncRNA classification attending to their localization. The enhancer, intronic, and intergenic lncRNAs contain their own promoters that are distinct from protein coding gene. Bidirectional lncRNAs share promoter with a protein coding gene and are transcribed from the opposite strand of the gene. Antisense (AS) lncRNAs have been involved in the transcriptional interference of the neighboring protein coding genes.
    In MM, dysregulated lncRNAs affect various aspects of the disease (Table 2). Several of them act as competing endogenous RNAs (ceRNAs), having miRNAs as targets and acting as miRNA sponges (Table 3) [72].
    Table 2. lncRNAs that are dysregulated in MM.
    1 Arrow up indicates overexpression of the lncRNA, and arrow down indicates underexpression of the lncRNA.
    Table 3. Genes dysregulated in MM due to overexpression of ceRNA lncRNAs.

    lncRNA

    miRNA

    Gene

    References

    ANGPLT1-3

    miR-30a-3p

    MAF

    [52]

    CRNDE

    miR-451

    IL6R

    [48][74]

    H19

    miR-29b

    HDAC4 and MCL1

    [65][76]

    MALAT1

    miR-509-5p

    FOXP1

    [66]

    miR-1271-5p

    SOX13

    [67]

    MEG3

    miR-181a

    BCL2L11

    [80]

    MIAT

    miR-29b

    HDAC4 and MCL1

    [65][81]

    NEAT1

    miR-214

    CD276

    [43]

    miR-193a

    MCL1

    [59]

    OPI5-AS1

    miR-410

    KLF10

    [27]

    PRAL

    miR-210

    DIMT1

    [31][32]

    SNHG16

    miR-342

    RUNX2

    [88]

    UCA1

    miR-331-3p

    IL6R

    [54]

    miR-1271-5p

    SOX13 and HGF

    [68]

    4.3. Other ncRNAs

    The impact of ncRNA dysregulation in MM goes beyond the well-studied miRNAs and lncRNAs. piRNAs constitute a very recent family of 24-31 nucleotide RNAs that can be abnormally expressed in various cancers. piRNA-823 is the only described example of its kind involved in MM pathogenesis so far [90]. Its overexpression was associated with a poor prognosis, suggesting that its detection could be part of a suitable risk stratification strategy. The oncogenic action of piRNA-823 seemed to be mediated through de novo methylation, as its overexpression was associated with DNMT3A/3B expression levels in primary MM cells [91]. Moreover, levels of piRNA-823 were higher in extracellular vesicles shed by MM cells, suggesting that this may promote proliferation, angiogenesis, and invasion in endothelial cells [90]. These findings reinforce the importance of cellular communication between MM cells and the microenvironment, also via piRNAs.
    snoRNAs are also relevant in cancer development. Beyond their canonical function in rRNA processing, mRNA splicing and editing, as well as stress responses, they are involved in pathological processes such as cell transformation, tumorigenesis, and metastasis. The most important finding about snoRNAs in MM involved ACA11, an orphan box H/ACA snoRNA encoded within an intron of MMSET [92]. ACA11 was found to be localized into nucleoli and bound to a small nucleolar ribonucleoprotein (snRNP). This led to the downregulation of ribosomal protein genes that are associated with the control of oxidative stress [93]. Recently, new studies showed that ACA11 upregulated ribosome biogenesis in a reactive oxygen species-dependent manner, suggesting that the increased level of protein synthesis driven by ACA11 made MM cells more sensitive to proteasome inhibitors [94]. Moreover, elevated levels of tRNA were seen in MM cells to accommodate their increased need for protein translation machinery [95]. Therefore, it is reasonable to state that the detection of this snoRNA could help assess the efficacy of a bortezomib-based therapy.
    Recently, circRNAs has been seen as a promising new therapeutic approach for MM. circRNAs are covalently-closed RNAs due to the junction of their 5′ and 3′ ends, which can remain relatively stable in the cytoplasm. This closed structure confers them an important variety of functions, such as acting as miRNA sponges, interacting with RNA binding proteins, or acting as scaffolds for the formation of enzyme-substrate complexes. circRNAs were identified as being key regulators of some hallmarks of cancer, including unaltered growth, apoptosis evasion, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, as well as stemness [21]. A recent analysis of the genome wide profiling showed circRNA expression patterns in MM [96]. circ_0000190 was found to negatively regulate miR-767-5p in the cytoplasm and to inhibit cell viability, proliferation, and MM progression in both in vitro and in vivo models through the MAPK4 pathway [61]. Besides, circ-CDYL was found to regulate miR-1180 and to overexpress YAP, ultimately triggering MM uncontrolled growth [63]. The duality of functions between suppressive and inductive tumor roles is also present in circRNAs and some were proposed as possible biomarkers. hsa_circ_0007841 was upregulated in MM cell lines, but also differentially expressed in MM patients depending on their staging. Besides, it targeted several miRNAs regulating bortezomib sensitivity and osteoclast differentiation [97]. The newly described hsa_circ_0003489 induced the overexpression of HDAC1 by sponging its repressor, miR-874-3p, and maintaining cell viability and proliferation. Its knock-down led to a sensitivity to bortezomib [62]. These new findings reinforce the idea that circRNAs could be suitable molecular targets in innovative therapies against MM and that their detection could be valuable for assessing and monitoring MM development in patients.

    5. Conclusions

    Recent findings on epigenetic and ncRNA alterations involved in MM have suggested their importance in the development and progression of the disease. A considerable amount of these dysregulations affects crucial pathways implicated in the cell cycle, proliferation, genomic stability, angiogenesis, and hypoxia. Besides, the identification of ncRNA biomarkers suggests their potential use as efficient diagnosis and prognosis tools. However, more research is still required. The emergence of techniques such as CRISPR-Cas opens the way for possibilities to develop new treatments and improve the outcome of MM patients.

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      Perez, R.R.; Cuendet, M.; Coira, I.F. Epigenetics and Non-Coding RNAs in Multiple Myeloma. Encyclopedia. Available online: https://encyclopedia.pub/entry/23565 (accessed on 07 February 2023).
      Perez RR, Cuendet M, Coira IF. Epigenetics and Non-Coding RNAs in Multiple Myeloma. Encyclopedia. Available at: https://encyclopedia.pub/entry/23565. Accessed February 07, 2023.
      Perez, Rafael Rincon, Muriel Cuendet, Isabel F. Coira. "Epigenetics and Non-Coding RNAs in Multiple Myeloma," Encyclopedia, https://encyclopedia.pub/entry/23565 (accessed February 07, 2023).
      Perez, R.R., Cuendet, M., & Coira, I.F. (2022, May 30). Epigenetics and Non-Coding RNAs in Multiple Myeloma. In Encyclopedia. https://encyclopedia.pub/entry/23565
      Perez, Rafael Rincon, et al. ''Epigenetics and Non-Coding RNAs in Multiple Myeloma.'' Encyclopedia. Web. 30 May, 2022.
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