MYC is embedded in the transcriptional oasis of the 8q24 gene desert. A plethora of genomic elements has roles in MYC aberrant expression in cancer development by interacting with transcription factors and epigenetics regulators as well as altering the structure of chromatin at the MYC locus and tissue-specific long-range enhancer–promoter contacts. Furthermore, MYC is a master regulator of several human cancers by modulating the transcription of numerous cancer-related genes through epigenetic mechanisms. This review provides a comprehensive overview of the three-dimensional genomic organization around MYC and the role of epigenetic machinery in transcription and function of MYC as well as discusses various epigenetic-targeted therapeutic strategies in MYC-driven cancers.

Myelocytomatosis proto-oncogene (c-MYC) is one of the scarce protein-coding genes located in human chromosomal band 8q24, a region known as gene desert (1). The expression of MYC is regulated by several enhancers located in the 2.8 Mb topologically associating domain (TAD) on chromosome 8q24 where MYC is also located (2). Transcription of MYC mediates from four alternative promoters (P0, P1, P2, and P3; ref. 3). Also, a G-quadruplex–forming sequence is located upstream of the P1 promoter that accounts for the regulation of MYC expression (4, 5). The large clusters of enhancers at both sides of MYC mediate tumor-specific chromosome looping with promoters. The presence of a conserved CCCTC-binding factor (CTCF) binding site 2 kb upstream of MYC, known as enhancer-docking site, is necessary for forming enhancer–promoter loops (2, 6). Inactivation of this element can perturb the chromosome looping and result in a reduction of MYC expression (7). Furthermore, multiple lines of evidence have shown several chromatin-associated long noncoding RNAs (lncRNA) have roles in transcriptional regulation of MYC through the promotion of chromosome looping and regulation of polycomb repressive complex (PRC) subunits function possibly through forming triple helix structures (8–10).

Similar to the other members of MYC super-transcription factor family (MYCL and MYCN), c-MYC contains a basic helix–loop–helix leucine zipper domain, which is essential for its functional form through heterodimerization with MYC-associated factor X (MAX; refs. 11, 12). c-MYC regulates the transcription of numerous cancer-related genes via binding to the conserved DNA sequences of their promoter called E-boxes (13, 14). Hence, mutations and dysregulation in MYC expression are the hallmark of up to 70% of all human cancers (15–17) and implicated in the regulation of cell-fate decisions including cell cycle, proliferation, apoptosis, and metabolism (18–20). MYC functions also as a regulator of the cancer epigenome by recruitment of chromatin modifiers including histone acetyl-transferase (HAT) complexes and ATP-dependent chromatin-remodeling complexes to whether activate or prevent the transcription of target genes (21–23).

MYC is an “undruggable” target, which means it cannot be targeted pharmacologically (24, 25). Because of the importance of epigenetic machinery in the regulation of MYC expression and function in cancer cells, conspicuously regulation of epigenetic modifiers that alter the DNA and chromatin structure show signs of promise toward MYC-induced cancer therapy.

This revised view tries to shed light on the complexity of regulation of MYC expression with insights of chromatin landscape and genomic elements as well as roles of epigenetic-targeted therapeutic strategies in MYC-driven cancers.

MYC is a key transcription factor that controls the expression of a variety of genes involved in the cell cycle, cell growth, differentiation, transformation, genomic stability, and angiogenesis by binding to their regulatory sequences (26, 27). Precise MYC expression has also a vital role in facial morphogenesis, which is influenced by the intact function of multiple enhancers of MYC (28). MYC is embedded inside the TAD, a region with multiple regulatory elements including a large specific super-enhancer (comprising a set of enhancers) and several CTCF-binding sites (subTADs) upstream of MYC promoter (2). It is noteworthy that genome-wide association studies (GWAS) showed that many genetic variants located at 8q24 influence the expression levels of MYC and increase individuals' susceptibility to several diseases especially cancer by abrogating promoter–enhancer interactions (29, 30). In this view, a recent study has shown that rs4645948 (C>T) and rs2071346 (G>T) that are located in 5′-untranslated region (UTR) and intron of MYC, respectively, might put individuals at higher risk of nasopharyngeal carcinoma development. Moreover, rs4645948 might exert a regulatory effect on MYC active promoter region, as individuals with CT and TT genotypes expressed higher levels of MYC, leading to nasopharyngeal carcinoma progression (31). Interestingly, recent evidence has shed some light on the role of rs6983267 located in the gene desert around MYC, in colorectal and prostate cancer pathogenesis. Further study has unveiled that rs6983267-containing region is significantly associated with colon and prostate cancer through interacting with MYC promoter and regulating its expression (30, 32). Intriguingly, being located 330 kb from the c-MYC gene, within TCF4 binding site, rs6983267, could increase the susceptibility to colorectal cancer by potentiating TCF4 binding and upregulation of c-MYC in a cis-regulatory manner (33). Also, a GWAS study has revealed several ovarian cancer–associated SNPs map to 8q24. It has been shown that rs1400482 with the major allele G is strongly associated with increased risk of ovarian cancer, especially serous ovarian cancer (P = 2.5 × 10–13; ref. 34). Furthermore, a study on patients with non-Hodgkin lymphoma suggested that the frequencies of GG genotype at rs121918684 and CC genotype at rs775522201 at c-MYC locus were strongly associated with disease development (35). In contrast, neither rs4645943 C > T located 2 kb upstream MYC transcription start site nor rs2070583 A > G located at 3′ UTR of MYC were associated with different cancers risk in Chinese population (36–38). Chromatin state and chromosome conformation mapping of K562 cells by clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) identified seven enhancers (e1–e7) along with two repressive elements (r1, r2) within 1.2 Mb sequence of MYC that probably repress MYC expression. Moreover, high-throughput chromosome conformation capture (Hi-C) and chromatin interaction analysis by paired-end tag (ChIA-PET) in K562 cells revealed that each enhancer may interact with MYC promoter (39). Correspondingly, Hi-C analysis of GM12878 and CD34+ cells showed that enhancers and MYC promoter interact with each other in three-dimensional (3D) spaces. These interactions occur within 1 Mb surrounding MYC in GM12878 cells, whereas in CD34+ cells, they are limited to the downstream region of MYC (40). MYC probably has a transcriptional enhancer activity as well as autonomously replicating activity in a positive feedback manner in human cells such as HL-60 by binding to an autonomously replicating sequence (ARS) located upstream of MYC coding region (41). A region known as a super-enhancer is also located 1.7 Mb downstream of MYC and plays a crucial role in both normal hematopoiesis and leukemia stem cell hierarchies. Disruption of this super-enhancer was shown to lead to the downregulation of MYC in hematopoietic stem cells, and thereby increase of differentiation-arrested multipotent progenitors (42, 43). Recently, this super-enhancer region has been renamed as a blood enhancer cluster (BENC), which is conserved among mice and humans and may cause leukemia by modulating MYC expression (2, 43). During mice hematopoiesis, BENC regulates MYC expression by increasing the chromatin accessibility and interacting with MYC promoter in a three-dimensional loop manner. Correspondingly, mice with a homozygous deletion in BENC demonstrated a significant reduction in bone marrow cellularity, self-renewal, proliferation, and differentiation of hematopoietic stem cells (Fig. 1; refs. 2, 43). Injection of polyinosinic: polycytidylic acid [poly(I:C)] into acute myeloid leukemia (AML)–induced mice model to impair BENC activity caused leukemia onset delay and overall survival increase, which confirms the essential role of BENC in controlling MYC expression (43). An increasing body of evidence also revealed a gene desert on chromosome 8q24 close to MYC oncogene, comprising several risk loci to multiple cancers including myeloma, chronic lymphocytic leukemia, pancreatic, thyroid, bladder, prostate, breast, and colon (44–47). Taken together, it is noteworthy that the expression of MYC is regulated via its promoter interaction with several cis-regulatory elements, and any disruption in these interactions may result in severe disorders especially cancer (33, 48).

Figure 1.

MYC enhancer cluster regulates normal and leukemic hematopoietic stem cells. A, Super-enhancer interacts with MYC promoter, and CTCF–CTCF interaction generates an insulated TAD, thereby regulating MYC transcription in a two-dimensional chromatin structure. B, BENC regulates MYC expression by interacting with MYC promoter in a three-dimensional loop during normal hematopoiesis. C, BENC disruption causes significant reduction in differentiation of hematopoietic stem cells and promotes leukemia. A–I, different BENC modules; TTS, triplex target site.

Figure 1.

MYC enhancer cluster regulates normal and leukemic hematopoietic stem cells. A, Super-enhancer interacts with MYC promoter, and CTCF–CTCF interaction generates an insulated TAD, thereby regulating MYC transcription in a two-dimensional chromatin structure. B, BENC regulates MYC expression by interacting with MYC promoter in a three-dimensional loop during normal hematopoiesis. C, BENC disruption causes significant reduction in differentiation of hematopoietic stem cells and promotes leukemia. A–I, different BENC modules; TTS, triplex target site.

Close modal

MYC has been known as a central regulator of the transcription process through chromatin remodeling (22). MYC exerts its effect through recruiting two major protein complexes including HAT complexes and ATP-dependent chromatin-remodeling complexes (21). MYC interacts with multiple HATs such as Gcn5-related N-acetyltransferase (GCN5), and tat-interactive protein 60 (Tip60) via transformation/transcription domain–associated protein (TRRAP; Supplementary Fig. S1; refs. 49, 50), which is a subunit of the HAT and acts as an essential cofactor in MYC–HAT interaction (51). MYC promotes chromatin reposition from the nuclear periphery, and thereby chromatin decondensation via HAT-mediated histone acetylation (52). Also, MYC induces acetylation of several lysine residues including H3K14, H3K18, H3K9, H4K5, H4K12, and significantly H4K8 and H4K9, on its target promoters (53). Accumulating evidence revealed that MYC also interacts with other HATs such as GCN5/PCAF and p300/CREB-binding protein (P300/CBP; refs. 54–56). General loss of histone acetylation, increasing histone methylation, and chromatin condensation in N-myc null cerebellar granule neural progenitors (CGNPs) probably highlight the fundamental role of MYC in chromatin remodeling through histone acetylation (23). Following the creation of c-Myc-knockdown model (Raji-KD) the cyclin-dependent kinase 1 (Cdk1) and cyclin B1 expression decreased significantly, and caused G2–M arrest. Therefore, the Raji-KD study showed that c-MYC plays a fundamental role in regulating CDK1/cyclin B1–dependent-G2–M cell-cycle progression by recruiting TIP60/males absent on the first (MOF) to acetylation of H4 (57). Furthermore, there are some reports about the relationship of MYC with chromatin-remodeling processes via interaction with INI1 (SMARCB1/hSNF5/BAF47) a core member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex (58). It was also shown that the basic helix–loop–helix region associated with MYC interacts with INI1 repeat 1 (Rpt1) to chromatin organization and transactivation in an ATP-dependent manner (59). On the other hand, following B-cell differentiation, chromatin interactions are limited to predominantly short-range contacts within increased CTCF-mediated loops. Significant reduction in loop contacts in Myc−/− and oligomycin-treated cells emphasized on probable effects of MYC in SWI/SNF–mediated chromatin remodeling (52). Evidence showed that the 3D remodeling of the genome and intradomain interactions might be influenced by ncRNAs (60, 61). CCAT1-L, a colorectal cancer–specific lncRNA is transcribed from a distal enhancer, and is located 515 kb upstream MYC. CCAT1-L facilitates chromosome looping and MYC promoter–enhancers interactions by interacting with CTCF (62). These findings shed some light on the crucial role of MYC in regulating chromatin shape in a 3D structure.

It is becoming increasingly clear that perturbation in MYC expression is associated with immune disorders including myasthenia gravis, psoriasis, pemphigus vulgaris, and atherosclerosis as well as a broad spectrum of cancers (16, 63–65). Evidence showed that several processes including chromosomal rearrangement, gene duplication, noncoding RNAs (ncRNA; lncRNAs, miRNAs, etc.; Supplementary Table S1), enhancer disruption, disturbance in CTCF-binding site, and DNA modification (DNA methylation and histone acetylation, etc.) are involved in MYC expressions' dysregulation. Interestingly, it was reported that MYC expression is controlled both at transcriptional and posttranscriptional levels (66, 67).

MYC rearrangements

MYC rearrangements have been identified in several types of leukemia and lymphoma (68–70). Chromosomal translocation (8;14)(q24;q11) (MYC and immunoglobulin heavy chain) has been long linked to Burkitt lymphoma through MYC overexpression (71). MYC rearrangement along with JAK2 V617F mutation was reported in two patients with myelodysplastic syndrome/acute myeloid leukemia (MDS/AML; ref. 72). Recently, t(8;14)(q24;q32) IGH/MYC translocation was identified in three adult cases with B lymphoblastic leukemia/lymphoma (B-ALL/LBL) along with Burkitt lymphoma–like morphology (73). Consistently, the study of bone marrow transplantation in murine stem cell virus model showed that Myc induced AML in all transplanted mice with antiapoptotic mutation, whereas AML/ALL mixture was seen when apoptosis was inhibited (74).

CTCF elements

Mechanisms underlying enhancer–promoter transactivation remain to be fully elucidated. However, accumulating research has shown that CTCF-binding motifs inside the MYC TAD have strong insulation ability in the separation of adjacent regions and mediate the formation of physical contacts that involve DNA looping between enhancers and MYC's promoter to activate its expression (7, 75, 76). Strikingly, deletion of the CTCF-binding site located 2 kb upstream of the MYC promoter suggested that this site plays a role in the protection of the promoter from DNA methylation, but may not play a role in inhibiting transcription (77). Interestingly, the upstream CTCF-bound site provides an enhancer-docking site, facilitating the interaction of transcriptional factors and chromatin complexes to activate and hijack MYC promoter, which is critical for the proliferation of cancer cells (7, 77). The enhancer-docking site is a hypomethylated CpG island because the CTCF binding is dependent on the level of DNA methylation, and is abrogated when it is methylated (7, 78).

NOTCH- and CTCF-binding site

NOTCH1 regulates enhancers and promoters through activation of CTCF (to mediate the loop structure) and recombination signal binding protein for immunoglobulin kappa J region (RBPJ) DNA-binding protein, to facilitate NOTCH binding to the promoter of its target genes (79).

Notch1-driven MYC enhancer (N-Me), a T-cell specific super-enhancer that resides approximately 1,500 kb downstream of c-MYC plays a crucial role in the development of T cells in T-cell acute lymphoblastic leukemia (T-ALL; ref. 80). The critical role of N-Me resides in the upregulation of NOTCH1-induced MYC expression via a loop structure with MYC proximal regulatory elements in the pathogenesis of T-ALL (81). Accordingly, mice with N-me deletion showed significant thymic atrophy, and reduction of CD4+CD8+ thymocytes (82). Amplifying NOTCH signaling mediated by NOTCH1 mutation facilitates T-ALL progression. In patients with T-ALL, NOTCH1 induces the expression of MYC via interacting with N-Me. N-Me duplication was also reported in some patients with T-ALL, highlighting the vital role of N-Me in T-ALL pathogenesis (81). Moreover, different studies disclosed multiple transcription factors including β-catenin, runt-related transcription factor 1 (RUNX1), STAT5, and T-cell leukemia homeobox 1 (TLX1), as well as NOTCH as being associated with N-Me, mediated MYC transcription regulation (83, 84).

WNT and CTCF-binding site

The stabilization of β-catenin and its translocation into the nucleus are involved in the canonical wingless (WNT) signaling pathway, which induces the upregulation of MYC, thereby regulating cellular proliferation. In the nucleus, β-catenin forms active transcriptional complexes with the members of the T-cell–specific transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) family and facilitates binding of the active complex to WNT-responsive DNA elements (WRE) located downstream and upstream of MYC gene (85). WREs regulate MYC expression via a large chromosomal loop structure with the MYC proximal promoter mediated by CTCF (86).

BORIS

BORIS (brother of the regulator of imprinted sites) encoded by CTCF-like (CTCFL) gene, is aberrantly expressed in various human cancers to promote cell proliferation and survival (87, 88), and as a mediator of cancer stemness plays an important role in epithelial-to-mesenchymal transition (EMT) as well as chemoresistance and recurrence (89). BORIS bound DNA at chromatin loop anchors in regulatory regions enriched with super-enhancers (90). At the upstream promoter region of MYC, BORIS and its binding partners, HLA-B–associated transcript 3 (BAT3), a co-chaperone recruiter, and SET domain-containing 1A (SET1A), an H3K4 methyltransferase, work together toward modifying chromatin conformation. It seems that BORIS creates a methylation-independent binding platform to increase the H3K4 dimethylation level at the promoter of MYC, leading to MYC upregulation (91).

MYC's upstream enhancers

Accumulating genomic studies have shown that multiple genetic markers reside at the 5′ end of MYC in TAD, and are associated with the risk of several human cancers (92–97). The results of these studies have indicated different genetic variations, including rs13254738 and rs6983561 in region 2 (chr8: 127,062,671–127,162,671; refs. 94, 98), rs6983267 and rs7000448 in region 3 (chr8: 127,389,527–127,458,527; refs. 94, 98), and rs1447295 and rs10090154 in region 1 (chr8: 127,458,528–127,537,878; refs. 93, 95), to cite a few, located upstream of MYC and associated with prostate and colorectal (rs6983267; refs. 32, 99) cancer risk. The existence of epigenetic marks of active enhancer (active histone modifications including H3K27ac and H3K4me2 or 3; refs. 100–102) has fueled the concept that these three independent regions may deem active tissue-specific enhancers (103, 104). Furthermore, recent advances have revealed that the region 3 plays a medulloblastoma-specific enhancer role because the MYC amplicon contains this region in this pediatric cancer (105).

Besides, multiple lines of evidence support that in addition to the N-Me in T-ALL (81, 106), the Notch signaling pathway is able to affect its direct target, MYC, through B-NDME (for B-cell Notch-dependent MYC enhancer) in B-cell malignancies (107). B-NDME resides between regions 2 and 3, approximately 500 kb upstream of MYC (108). The role of this B-cell lymphoma enhancer is illustrated by the existence of chronic lymphocytic leukemia (CLL)–associated SNPs (rs2466024 and rs2456449; ref. 109) as well as H3K27ac marks interacting with the MYC promoter in small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL; refs. 104, 107). Also, a recent report has corroborated that NOTCH1 forms 3D spatial clusters, or “3D cliques,” and impacts upstream enhancers/promoter contacts in MYC locus in triple-negative breast cancer (110). Altogether, these results have implied how 5′ enhancers along with downstream enhancers contribute to long-range chromatin looping (probably through transcription factors recruitment like NOTCH1) to hijack MYC expression in a tumor-specific manner.

G-quadruplex element

Multiple lines of evidence have supported the principal role of nuclease hypersensitivity element III1 (NHE III1) region of the c-MYC promoter in the regulation of MYC. NHE III1 element is located -142 to -115 nucleotides upstream of promoter 1, and accounts for almost 90% of c-MYC transcriptional control (111, 112). The region consists of five consecutive runs of guanine that fashion two intramolecular secondary structures in each strand, forming a G-quadruplex (G4) structure by Hoogsteen-base pairing that is stabilized by a monovalent cation such as Na+ or K+, and in the complementary cytosine-rich strand, an i-motif structure is formed by hemiprotonated C+-C base-pairing (113). However, the formation of the G-quadruplex structure needs higher Gibbs free energy than B-DNA duplex: the G4 structure of MYC promoter is highly stable through the existence of i-motif and its negative supercoiling as well as the stabilizing proteins such as nucleolin and nucleophosmin (114–116). Strikingly, the G4-forming sequences are highly conserved and devoid of disruptive SNPs, which could change the structure (117, 118). In the case of MYC, the parent sequence consists of 27 nucleotides (Pu-27). The sequence may be subjected to further modifications including truncations (Pu-19 and Pu-18) as well as substitution or subtractions (MYC-2345 and MYC22-G14T/G23T) to reduce the number of guanines (119).

Forming the G4 secondary structure, NHE III1 deemed a negative regulator of MYC transcription. The silencer nature of the NHE III1 region G-quadruplex is characterized by the prevention of Sp1 transcription factor binding and its implication in chromatin remodeling (120). Cell signals for MYC expression promote the recruitment of Sp1 to bind the duplex form of NHE III1 region. Sp1 binding results in NHE III1 denaturation with two outcomes: first negative supercoiling to free far upstream element (FUSE) of nucleosomes and melt it (121); second filling of the G- and C-rich single-stranded regions with MYC transcription factors, cellular nucleic acid-binding protein (CNBP), and RNA-binding protein hnRNP K (122, 123). The single-stranded FUSE further recruits FUSE-binding protein (FBP) and FBP-interacting repressor (FIR) to mediate a loop structure with the promoter region of MYC where transcription factor II H complex resides, to upregulate and maintain the MYC expression (Supplementary Fig. S2; ref. 124). Considering the crucial role of the G4 structure of the NHE III1 repressor element, mutations in the G4-forming sequence may potentially disrupt the stability of G-quadruplex (125). Conspiciously, evidence has secured a place for MYC G-quadruplex structure as a bona fide target for anticancer therapies. Recent advances in this field have revealed a benefit for using G4-stabilizing small molecules and proteins (reviewed in ref. 126) for chemotherapy.

ncRNAs

Studies of transcriptome profile of several tumor samples have revealed that ncRNAs control the expression of MYC, whereas some other ncRNAs are regulated by MYC at both transcriptional and posttranscriptional levels, and thereby induce tumor progression (10, 127, 128). Correspondingly, 1,273 noncoding transcripts were detected in B-cell line P493-6 (that overexpresses MYC), among which, 296 and 238 were significantly upregulated and downregulated, respectively, by more than 2-fold (P < 0.001). Furthermore, out of 296 upregulated lncRNAs, 8 including differentiation antagonizing non–protein-coding RNA (DANCR), miR-17–92a-1 cluster host gene (MIR17HG), small nucleolar RNA host gene 15 (SNHG15), SNHG16, minichromosome maintenance complex component 3–associated protein (MCM3AP-AS1), USP2 antisense RNA 1 (USP2-AS1), KTN1 antisense RNA 1 (KTN1-AS1), and VPS9D1 antisense RNA 1 (VPS9D1-AS1) were remarkably upregulated by more than 8-fold (127). An increasing body of evidence revealed that distinct lncRNAs are expressed in the 8q24 gene desert region in different human tumors (129–131). LncRNA cancer–associated region lncRNA 5 (CARLo-5) is transcribed in the 8q24 gene desert and was shown to cause colorectal cancer development through inhibiting G1 arrest. Also, cancer-associated variant rs6983267 mapping to the MYC enhancer region regulates CARLo-5 expression by direct long-range interaction of MYC enhancer with CARLo-5 promoter (132). LncRNA colon cancer–associated transcript 2 (CCAT2) is another noncoding transcript associated with highly conserved 8q24 region encompassing colorectal cancer susceptibility variant rs6983267. CCAT2 induces chromosomal instability, tumor growth, and metastasis in microsatellite-stable colorectal cancer through activating TCF7L2-mediated WNT and its target genes such as MYC. Further investigation demonstrated that CCAT2 exerts its metastatic effects through increasing two miRNAs including miR-17–5p and miR-20a, which are located downstream of MYC. Accordingly, subcutaneous transplantation of CCAT2-overexpressing HCT116 cells in Swiss nu-nu/Ncr nude mice induced larger tumors in comparison with empty vector–transduced cells, while its injection into the spleen caused higher liver metastasis rate in comparison with the control group (131). CCAT1-L (CCAT1, the long isoform) is located 515 kb upstream of MYC and is transcribed from a super-enhancer. CCAT1-L facilitates long-range intra-chromosome interactions between the MYC promoter and its upstream enhancers through interaction with CTCF. Consistently, recruiting chromosome conformation capture (3C) assay in HT29 cells showed that interaction between three chromatin regions including MYC-335/MYC, MYC-335/MYC-515, and MYC/MYC-515 decreased upon CCAT1-L knockdown (9). LncRNA gastric carcinoma high expressed transcript 1 (lncRNA-GHET1) promotes proliferation of gastric carcinoma through amplifying the interaction between insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) and c-Myc mRNA and thereby increases stability and expression of c-Myc mRNA (133). Surprisingly, MYC acts as lncRNA PVT1 activator by binding to the PVT1 promoter, and upregulating PVT1 expression in a positive feedback. Then, upregulated PVT1 promotes proliferation and viability of cervical cancer cells by sponging miR-486-3p (Supplementary Table S1; ref. 134). Interestingly, PVT1 promoter could exert a tumor-suppressive role in breast cancer cell lines independent of lncRNA PVT mechanism of action through competing for enhancers of neighborhood MYC gene, and thereby halting MYC promoter–enhancer interaction contributing to MYC downregulation (135). On the other hand, there are some miRNAs including miR-129-2, miR-101, miR-26a, and miR-29 implicated in 3D regulation of MYC transcription. miR-129-2 acts as a tumor suppressor, and is a negative target of MYC that blocks hepatocellular carcinoma proliferation and tumor growth by targeting a core component of the Warburg effect known as pyruvate dehydrogenase kinase (135). Furthermore, miR-26a impedes zeste 2 polycomb repressive complex 2 subunits (EZH2) and MYC to obstructing cell growth in lymphoma cells (136). Taken together, studies around the ncRNAs have shed some light on crucial role of lncRNAs and miRNAs in regulation of MYC 3D structure and expression, and consequently tumor progression. Moreover, it highlights the efficacy of these molecules as new promising biomarkers and potential efficient therapeutic targets in large number of malignancies.

Activation of MYC occurs via heterodimerization with MYC-associated factor X (MAX). Hence, both proteins are members of the basic helix–loop–helix leucine zipper (bHLH-zip) family, the dimerization results in an active transcription factor complex able of binding to DNA enhancer-box element (E-box) with CACGTG sequence as well as interaction with other transcription factors (137). At the posttranscriptional level, intracellular signaling cascades partner MYC to regulate tumor aggression processes. Among multiple intracellular signal transduction pathways, the oncogenic role of PI3K/AKT/mTOR and RAS/MAPK signaling axes are better described in MYC tumorigenesis. Mounting evidence implicated the roles of these two signaling pathways in tumorigenesis and chemoresistance pertained to the regulation of MYC function (138, 139). In cancer cells, both signaling pathways could be activated via RAS, leading to the degradation of MAX dimerization protein (MAD) a major antagonist of MYC (140). Having the basic helix–loop–helix leucine zipper domain, MAD competes with MYC for heterodimerization with MAX (141). As a kinase, ERK mediates phosphorylation of Ser62 of MYC to stabilize it and AKT inhibits GSK3b from leading to degradation of c-MYC (139, 142).

Regulatory functions of lncRNAs may be exerted through establishing interactions with DNA and proteins. At the transcriptional level, lncRNAs may bind to a specific sequence of the duplex DNA through Hoogsteen-based interactions (143, 144). Single-stranded lncRNA binds to the major groove of double-stranded DNA through purine-rich sequences via Hoogsteen or reverse Hoogsteen hydrogen bonds to form a triple helix RNA:DNA:DNA structure (145). These triple helical structures are necessary for some crucial features of lncRNAs, including recruitment of chromatin-modifying complexes, to inhibit gene expression or creation of a loop between the promoter of a gene and distal regulatory elements to the recruitment of multiple transcriptional factors for facilitating gene expression (146). Recent evidence has identified that most annotated human genes have at least one potential target sequence in their promoter or intron for triplex-forming molecules (147). Because MYC is located in a TAD region with multiple enhancers and active promoters, we speculated that interplay between lncRNAs and MYC at the transcriptional level may be affected by triple helix structures. We used Triplexator to detect triplex-targeting sequences of MYC locus, triplex-forming oligonucleotides of lncRNAs, and then checked for potential RNA–DNA triplex between lncRNAs and MYC (148). In this review, we examined the potential triplex-forming ability of some classic lncRNAs (e.g., HOTAIR, ANRIL, and H19), of which, their effect on the expression of MYC was previously defined.

Accumulating evidence has shown that maternally expressed 3 (MEG3) is a tumor suppressor lncRNA that plays a role in the regulation of various tumor-associated genes expression including the MYC gene (reviewed in ref. 149). Recent research has suggested that triplex-forming ability may be responsible for MEG3 tumor-suppressive effects (147, 150). MEG3 occupies a polypurine-rich sequence and guides the polycomb repressive complex 2 (PRC2) subunits to the specific region of its target gene promoter and exerts its inhibitory effect by interactions with chromatin. As a chromatin-interacting lncRNA, MEG3 has a role to promote H3K27me3, a repressive mark, in the promoter and enhancer region of its target through recruitment of enhancer of EZH2 and suppressor of zeste 12 protein homolog (SUZ12; ref. 151).

Telomerase RNA component (TERC, also known as TR) is the integral RNA component of telomerase, and is affiliated with the lncRNA class. As a fundamental part of the telomerase enzyme, TERC provides a template for telomerase reverse transcriptase (TERT) to add single-stranded telomere repeats to the end of chromosomes (152). However, the activity of TERC is not limited to the telomerase function. TERC can form a triple helical structure with the promoter of its target genes and regulate their expression (153). The existence of potential DNA-binding domains (DBD) in the TERC sequence, which is present in many genomic regions has suggested a functional triplex-forming role for TERC (150). Furthermore, the application of chromatin isolation by RNA purification (ChIRP) to define the genomic interactions of lncRNAs, has identified the TERC occupancy at the MYC promoter probably through a cytosine-rich sequence motif (154, 155).

Correspondingly, the lncRNA sequences were downloaded from the v19 release of the GENCODE database (MEG3: ENST00000451743.6 and TERC: ENST00000602385.1). The reference genome sequence of MYC and 2000 bases upstream (promoter) that correspond to the hg19 build of the human genome were downloaded from the UCSC Genome Browser. We used the best Triplexator parameters for MEG3: l10e20g40 and TERC: l10e20g70 (where l: length, e: maximum error-rate, and g: minimum G-content; ref. 150). Because only single-stranded regions of lncRNAs participate in the formation of the triple helix, we additionally used RNAplfold to predict the secondary structure of lncRNAs, and double-stranded regions were removed from the results (156). The results represent multiple potential triple helixes for the entire MYC sequence and its upstream promoter region (Supplementary Fig. S3).

The single-stranded regions in MEG3 were located around nucleotide 20 (domain 1) and 700 (domain 3) that interacted with MYC triplex target site (TTS), which do not overlap with the protein-binding domains for PRC2 subunits (EZH2 and SUZ12; ref. 157). Therefore, the predicted binding sites of MEG3 at MYC locus have proposed that the inhibitory effect of MEG3 may be mediated through RNA:DNA helices formation with GA-rich DNA motifs of MYC promoter and PRC2 recruitment to the promoter region. Interestingly, MEG3 targets the G-quadruplex–forming sequence of the NHE III1 region of the MYC promoter for forming triplex as a purine-rich sequence.

The analysis of RNAplfold has revealed the single-stranded domains of TERC (around nucleotide 30 and 330), which form a triplex with the MYC region. Supplementary Fig. S3 depicts targeted C-motifs embedded upstream and within intron 1 of the MYC locus. Considering the presence of these areas, TERC is likely to be involved in the regulation of MYC expression via forming a triple helix.

Because MYC is dysregulated in various cancers, understanding the precise molecular mechanisms by which lncRNAs regulate its expression will be a crucial step in exploring potential new avenues in cancer therapy.

MYC epigenetic–targeted strategies

Understanding the role of pathologic epigenetic alterations in DNA and protein modification has been broadly studied in tumorigenesis (158). Reversibility of these modifications fueled the interest to use epigenetic drugs (epidrugs) and epigenetic-targeted therapies in the treatment of human cancers with restoring normal gene expression profile (159). The contribution of epigenetic alterations to the aberrant architecture of the chromatin implicated in cancer progression and tumor cells resistance to chemotherapeutic drugs made epidrugs as a potential therapeutic paradigm for cancer.

As a master epigenetic regulator of cancer, MYC has a global impact on chromatin structure by recruitment of a plethora of chromatin modifiers on the promoter region of cancer-contributing genes. Also, the induction of MYC expression is regulated through epigenetic modulators (22). Hence, targeting MYC and its epigenetic mediators represent a viable therapeutic strategy for a wide range of cancers.

Bromodomain and extraterminal (BET) family proteins are a subgroup of bromodomain (BRD)-containing proteins. They are characterized as the chromatin-modifying factors that read epigenetic modifications and bind to acetylated lysine residues on histone to recruit other transcription factors and RNA polymerase II on the enhancers, promoters, and especially super-enhancers of oncogenes including MYC (160). Targeting BET via BET inhibitors (BETi) or small molecules, to avoid recruitment of other factors through blocking their lysine-binding pockets has emerged as a potential therapy in cancer (160). There is a growing list of BETi, which have shown therapeutic potential in clinical and preclinical experiments including JQ1 (161), I-BET151 (162), OTX015 (163), and AZD5153 (164) to cite a few. Furthermore, there is substantial evidence that proved BETi can be used in combination with other anticancer drugs to enhance the efficacy of treatment and reduce the chemotherapeutic resistance. Particularly, the compounds that block important signaling pathways partnered in the pathogenesis of MYC at transcriptional (Notch and Wnt signaling pathways) or posttranscriptional (RAS/MAPK and PI3K/AKT/mTOR) level as well as proteins involved in cell cycle (CDKs), which are required for MYC function and stabilization, were found to be efficient (Fig. 2).

Figure 2.

BETi combined therapy implementations in MYC-induced cancers. The figure represents multiple drugs and their specific targets used in combination with BETi at the transcriptional (A) and posttranscriptional (B) levels of MYC expression.

Figure 2.

BETi combined therapy implementations in MYC-induced cancers. The figure represents multiple drugs and their specific targets used in combination with BETi at the transcriptional (A) and posttranscriptional (B) levels of MYC expression.

Close modal

Tracing acetylation and deacetylation of nucleosomes have revealed the new clinical potentials in the treatment of multiple human cancers particularly MYC-driven cancers. HATs and histone deacetylases (HDAC) are well-known enzymes for controlling the landscape of chromatin accessibility through transferring and removing acetyl groups and creating epigenetic changes in histone and nonhistone proteins.

Studies suggested that CREBBP/EP300 (a BRD-containing HAT) mediates the ectopic expression of MYC through the IRF4/MYC axis (165). Besides, using CREBBP/EP300 BRD inhibitors resulted in the dislocation of the complex from MYC-binding site at enhancers via a decrease in the level of histone acetylation in hematologic malignancies (166).

Thus far, a great deal of HDAC inhibitors such as panobinostat and vorinostat (global HDAC inhibitors) and romidepsin (selective inhibitors of HDAC1 and HDAC2) have become FDA approved, and were utilized as a single agent or in combination with other therapeutic approaches. Correspondingly, Ree and colleagues examined the usage of vorinostat combined with radiotherapy for pelvic carcinoma in phase I clinical trial (167) and observed the downregulation of MYC in patients and xenograft models. Furthermore, Oki and colleagues have revealed in another phase I clinical experiment the impact of targeting HDAC in diffuse large B-cell lymphoma (DLBCL; ref. 168). They utilized CUDC-907 (HDAC and PI3K inhibitor) with and without rituximab (a mAb that targets the CD20 antigen on B cells) in patients with relapsed/refractory DLBCL with MYC alterations. The responses demonstrated the promising potential of CUDC-907 treatment (single or in combination) for MYC-altered patients.

Histone chaperones regulate nucleosome assembly and facilitate gene transcription, DNA replication, and repair (169–171) via loosening DNA and eviction of histones as well as exchanging histone variants (172). Targeting these complexes may turn out to synthetic lethal circumstances for the proliferation of cancer cells. High expression of facilitates chromatin transcription (FACT), a known key regulator of the MYC signal, has been found in a broad range of human cancers (173). Further preclinical experiments have indicated that targeting FACT in cancer cells through the short hairpin RNA (shRNA) and small-molecule curaxin class of anticancer drugs (e.g., CBL0100 and CBL0137) reduced the downregulation of MYC and inhibited tumor cells from entering in proliferation state (174, 175). Thus, hampering histone chaperones seemed to be a promising therapeutic target especially in combination with other anticancer drugs.

The process of histone methylation, which is referred to as transferring one, two, or three methyl groups on arginine or lysine residues of histones, impinges on the maintenance of the normal state of chromatin for the regulation of cell cycle and gene expression (176). A large body of evidence has suggested the aberrant expression of histone methyltransferases and demethylases in the progression of the tumor. Disruptor of telomere silencing 1-like (DOT1L) is a methyltransferase that catalyzes the transfer of one, two, or three methyl groups on H3K79. DOT1L might upregulate c-MYC probably through H3K79me2 in the promoter region of c-MYC in multiple myeloma (177). As a complex, DOT1L and c-Myc-p300 promote the expression of EMT-related factors in breast cancer (178). Inhibition and silencing of DOT1L via EPZ004777 (a selective inhibitor of DOT1L) and siRNA indicated a decrease in c-MYC expression in colorectal cancer xenograft models and cell lines (179). Inhibition of WD repeat–containing protein 5 (WDR5) is of special interest for cancer therapy because it has been shown to mediate chromatin remodeling for MYC-induced tumorigenesis. WDR5 works with H3K4 methyltransferases through its arginine-binding site, known as the WDR5-interaction (WIN) site, and plays pivotal roles in H3K4 trimethylation (an open state of chromatin), which is necessary for MYC functions in tumor formation and progression (180). Therefore, targeting WDR5 through small-molecule inhibitors of the WIN site has emerged as a therapeutic promise. So far, a myriad of WIN site inhibitors has been described including MM-401, MM-589, WDR5-0103, piribedil, and OICR-9429 (reviewed in ref. 181).

MYC is a key transcription factor that is highly dysregulated in many human cancers. Strikingly, MYC is located in the 8q24 gene desert that is prone to several rearrangements, such as translocation, amplification, and viral integration. This “desert” region around MYC is crammed with numerous regulatory elements, including promoters, a G-quadruplex sequence, super-enhancers, and binding sequences for epigenetic machinery. Mountain of evidence has revealed that epigenetic mechanisms including methylation, acetylation, and ncRNAs, such as lncRNAs, and miRNAs play a crucial role in cancer progression through regulation of MYC expression. Surprisingly, our in silico study have revealed the triplex formation between lncRNATERC and MEG3 and MYC regulatory elements. The highlighted role of MYC in development of a wide spectrum of cancers put it as potential therapeutic target to combat cancer. In the light of evidence, epigenetic modulators play a key role in MYC expression by influencing its promoter and surrounding regulatory elements interactions. Therefore, targeting epigenetic modulators might be a promising therapeutic strategy in cancer therapy area. Currently, several epidrugs have been FDA approved and developed to use alone or in combination with other chemotherapy medicines for clinical use. Nevertheless, using epigenetic-targeted therapy presents considerable challenges to treating cancers because they may inadvertently lead to off-target effects and dysregulate crucial biological signaling pathways in the normal cell. Besides, the efficacy and safety of new therapeutic approaches need to be tested via costly and time-consuming clinical trials that represent a major challenge in cancer epigenetic therapy.

No disclosures were reported.

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Supplementary data