Jeyshka M. Reyes-González
Pablo E. Vivas-Mejía- 1Center for Collaborative Research in Health Disparities, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico
- 2Department of Biochemistry, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico
- 3Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico
Ovarian cancer is the deadliest of gynecological malignancies with approximately 49% of women surviving 5 years after initial diagnosis. The standard of care for ovarian cancer consists of cytoreductive surgery followed by platinum-based combination chemotherapy. Unfortunately, despite initial response, platinum resistance remains a major clinical challenge. Therefore, the identification of effective biomarkers and therapeutic targets is crucial to guide therapy regimen, maximize clinical benefit, and improve patient outcome. Given the pivotal role of c-MYC deregulation in most tumor types, including ovarian cancer, assessment of c-MYC biological and clinical relevance is essential. Here, we briefly describe the frequency of c-MYC deregulation in ovarian cancer and the consequences of its targeting.
Introduction
Ovarian cancer is the most lethal gynecologic malignancy with an estimated 21,410 new cases and 13,770 deaths expected for 2021 in the United States (1). According to the tissue of origin, ovarian tumors are classified into epithelial and non-epithelial types (2). Tumors that arise from germ and sex cord stromal cells in the ovaries constitute ~10% of ovarian cancers (3). Epithelial-derived ovarian tumors account for ~90% of ovarian cancers and can be subdivided into four major histological subtypes including serous, endometrioid, clear-cell, and mucinous carcinomas (3). Of these types, high-grade serous tumors (HGSOC) are the most commonly diagnosed (3). Despite advances in surgical and therapeutic options for ovarian cancer, resistance to platinum-based chemotherapy remains a major clinical challenge. Several mechanisms of platinum resistance have been proposed, including the altered expression of oncogenes such as c-MYC (4, 5).
c-MYC was discovered four decades ago as the human cellular homolog of the avian myelocytomatosis viral oncogene (v-myc) (6–10). Further studies strongly linked c-MYC to cancer, marking it as a bona fide human oncogene (11, 12). Following the initial discovery of c-MYC, genomic amplification of two additional human paralogs N-MYC and L-MYC were identified in neuroblastoma and small-cell lung cancer, respectively (13–15).
Oncogenic c-MYC arises through multiple molecular mechanisms at the DNA, RNA and protein levels, rendering c-MYC no longer dependent of control signals (16–19). c-MYC deregulation reprograms gene expression and promotes uncontrolled cell proliferation – one of the hallmarks of cancer (16, 20–22). Given its pivotal role as a driver in cancer progression and maintenance, as well as its association with drug resistance, c-MYC has become an ideal target for cancer therapy (19, 22, 23). However, given the lack of enzymatic activity and the absence of surface domains suitable for most pharmacological inhibitors, c-MYC is considered an “undruggable” protein (24, 25). Nevertheless, several strategies have been employed to inhibit c-MYC transcription, disrupt c-MYC/MAX dimerization, or prevent binding of c-MYC/MAX heterodimers to enhancer box (E-box) DNA sequences (19). Antisense oligonucleotides and RNA interference (RNAi) directed against c-MYC, as well as, inhibitors targeting c-MYC upstream and downstream signaling pathways have also been evaluated (19).
c-MYC Function and Regulation
c-MYC is a basic helix-loop-helix leucine zipper (bHLHZ) transcription factor that regulates the expression of ~15% of all human genes (26). Binding of c-MYC to promoter regions of target genes at E-boxes (including the 5′-CACGTG-3′ consensus sequence and other non-consensus sites) requires dimerization with its protein partner, MAX (27, 28). Upon DNA binding, c-MYC/MAX heterodimer recruits co-factors required for transactivation of gene expression (26, 29). As a transcription factor, c-MYC plays a central role in the control of several essential functions including proliferation, growth, cell-cycle progression, angiogenesis, metabolism, differentiation, apoptosis, cell adhesion and motility, among others (16, 20, 26, 30–32). In addition, c-MYC may repress gene expression through interaction with MIZ-1, SP1/SP3, and NF-YB/NF-YC transcription factors (33).
In normal (non-transformed) cells, c-MYC expression is tightly regulated at multiple levels (34). Transcriptionally, c-MYC is controlled by numerous transcription factors (including CNBP, FBP, and TCF), enhancers, and non-B DNA structures such as G-quadruplexes (35, 36). Post-transcriptional regulation of c-MYC is exerted by RNA-binding proteins (CELF1 and HuR) and non-coding RNAs (35, 37). Post-translationally, c-MYC stability and transcriptional activity are controlled by a variety of different proteins (33). Phosphorylation at Serine 62 (Ser62) by Ras-activated ERKs stabilizes c-MYC and promotes activation (38). Subsequent phosphorylation at Threonine 58 (Thr58) by GSK3β leads to PP2A-mediated dephosphorylation at Ser62 and ubiquitination by Fbw7, resulting in c-MYC proteosomal degradation (38). Oncogenic activation of c-MYC is commonly induced by gene amplification or translocation, transcriptional upregulation, and enhanced protein stabilization (16, 35).
c-MYC Deregulation in Ovarian Cancer
c-MYC Gene Amplification
c-MYC is located in chromosome 8q24, which is frequently translocated or amplified in cancer (39). In fact, integrated genomic analyses of ovarian carcinoma revealed that one of the most common focal amplifications resides within the region containing c-MYC (40). Early reports by Yasue et al., using Southern blot hybridization, showed that c-MYC was amplified in human ovarian tumor cell lines (41). Later, Zhou et al. reported c-MYC amplification in 25% of ovarian tumors, mainly papillary serous adenocarcinomas (42). Additional studies found c-MYC amplification in ~20–50% of ovarian carcinomas (43–54). In contrast, Smith et al. found no evidence of c-MYC rearrangement or amplification in tissues from serous adenocarcinomas (55). Nevertheless, Ross et al. identified c-MYC amplification as a potentially targetable genomic alteration in patients with relapsed epithelial ovarian cancer (EOC) (48).
By using fluorescent in situ hybridization (FISH) on ovarian tumor tissue arrays, Dimova et al. reported a high frequency for c-MYC copy-number increases (38.5%), including 22.1% amplifications and 16.4% gains (47). In addition, c-MYC copy-number changes were associated with the degree of malignancy and histological type (47). Similarly, by using next-generation sequencing (NGS), Du et al. found that c-MYC had a high frequency of copy-number variations (29%) in tumors from recurrent ovarian cancer patients (56). Surprisingly, by using quantitative PCR (qPCR) analysis, Yamamoto et al. observed significantly higher c-MYC copy-numbers in early-stage EOC, however, low c-MYC copy-numbers were associated with a statistically significant poor prognosis (57).
Darcy et al. found limited predictive or prognostic value of c-MYC gene amplification and polysomy for chromosome 8 in women with suboptimally-resected, advanced-stage EOC (58). In contrast, Wang et al. reported a trend toward poorer survival for ovarian cancer patients with c-MYC amplification (51). In fact, survival was significantly poorer in patients with amplification of both HER-2/neu and c-MYC oncogenes (51). Similarly, a study by Katsaros et al. found that patients with c-MYC amplification and high p185/p21 co-expression had a significantly worse survival than those with normal levels (52). Moreover, Jung et al. reported an association between c-MYC amplification with late stage and high grade in endometrioid EOC (59). However, c-MYC amplification had no impact on clinical outcome in serous and endometrioid tumors (59). Diebold et al. found no correlation between c-MYC amplification and histological tumor type, histological grade, FIGO stage, DNA ploidy, proliferative activity or prognosis (50). Similar results by Baker et al. showed no apparent relationship between c-MYC amplification and tumor grade, response to platinum-based chemotherapy, hormone receptor status, or initial CA-125 levels (46). Taken together, these observations suggest that although c-MYC gene copy-number variation and amplification have been commonly reported in ovarian cancer, a relationship between c-MYC gene aberrations and prognostic or clinicopathological significance has not been clearly established.
c-MYC mRNA Expression
Early studies by Slamon et al., using Northern blotting, showed that c-MYC transcript levels were higher in human ovarian adenocarcinomas compared to normal tissues (60). Similar reports showed that c-MYC mRNA levels were higher in early-stage ovarian cancer tissues compared with those in normal samples, as evident by qPCR analysis (57, 61). In fact, Kohler et al. found that c-MYC mRNA expression was increased in 47.6% of ovarian carcinomas (62). Similarly, a study by Tashiro et al. revealed that c-MYC transcripts were overexpressed in 37.5% of ovarian tumors (including 63.6% of serous adenocarcinomas) relative to normal ovarian tissues (63). Moreover, significantly higher c-MYC expression was observed in stage III compared with stage I and stage IV tumors (63). On the other hand, a study by Bauknecht et al. showed high c-MYC mRNA expression in 28% of ovarian carcinomas (64). An association between c-MYC gene amplification and high mRNA expression levels was also observed (59, 64).
Tanner et al. found no significant association between c-MYC mRNA expression in EOC and clinical parameters including metastatic spread, survival time, FIGO stage, or histological grade and type (65). Similarly, Yamamoto et al. found no significant difference between c-MYC mRNA expression levels and survival rate for early-stage EOC (57). Jung et al. also reported no relationship between high c-MYC mRNA expression and patient outcome in serous and endometrioid tumors (59). On the other hand, a study by Iba et al. comprising EOC specimens from patients who underwent the standard of care revealed that responders had higher c-MYC mRNA levels than nonresponders, and a better 5-year survival rate (66). In contrast, analysis of HGSOC data from The Cancer Genome Atlas (TCGA) revealed significantly worse disease-free (DFS) and overall (OS) survival in patients with high c-MYC mRNA levels (67). Overall, the clinical significance of c-MYC mRNA expression in ovarian cancer has been inconsistent.
c-MYC Protein Expression
Expression of the c-MYC protein had been previously detected in ovarian carcinoma tumor and stromal cells by immunohistochemical methods (IHC) (62). Using the same approach, Skírnisdóttir et al. observed positive staining for c-MYC in 76% of cases from early-stage EOC (68). Positivity status was associated with tumor grade (68). Similarly, Chen et al. found that c-MYC protein was overexpressed in 65.9% of cases from EOC compared to normal ovary; however, no significant difference was observed between histological subtypes (69). Plisiecka-Hałasa also observed a high incidence of c-MYC overexpression in endometrioid and clear-cell carcinomas (70). By using flow cytometry, van Dam et al. found that c-MYC protein was overexpressed in 35% of epithelial ovarian carcinomas (71). A similar study by Watson et al. showed that serous papillary ovarian carcinomas expressed significantly higher nuclear c-MYC protein levels compared with normal ovary (72).
Reports by Sasano et al. revealed no significant correlation between c-MYC intracellular distribution and nuclear and histological grade or mitotic activity in ovarian carcinomas (73). Nevertheless, studies in ovarian mucinous tumors showed that positive c-MYC protein expression and distribution correlated with tumor size and tumor classification, respectively (74, 75). However, retrospective analysis of clinical data suggested that a standard histological criteria is a more accurate indicator of tumor behavior than assessment of the pattern of c-MYC expression based on immunostaining alone (75).
Paradoxically, Plisiecka-Hałasa et al. found that c-MYC overexpression was associated with better tumor differentiation, higher p27, and lower Ki-67 expression in ovarian carcinomas treated with platinum-based regimens (70). On the other hand, Ning et al. found that increased nuclear c-MYC expression in early-stage ovarian cancer correlated with clinical stage and shorter overall survival (61). However, a study by Curling et al. showed no significant association between c-MYC protein and prognosis in ovarian carcinomas (76). Similarly, Jung et al. found no relationship between high c-MYC protein expression levels and patient outcome in endometrioid tumors (59). Yamamoto et al. also reported no significant difference in survival rate for c-MYC protein expression in early-stage EOC (57). Nevertheless, a positive association between phosphorylated c-MYC (Ser62) and expression of proliferation markers such as Ki-67 was observed (57). In addition, high phosphorylated c-MYC was associated with relatively poor prognosis (57). Similar to amplification and mRNA expression, the association between c-MYC protein levels and clinical parameters in ovarian cancer is not clear. Assessment of the clinical relevance of phosphorylated c-MYC in ovarian cancer warrants further investigation.
Targeting c-MYC in Ovarian Cancer
Antisense Oligonucleotides
Early reports showed that targeting c-MYC in vitro with triplex-forming (TFOs) and liposomal phosphorothioate oligonucleotides (PTOs) inhibits ovarian cancer cell growth (77, 78). In fact, evidence indicates that PTOs against c-MYC inhibit the proliferative effect of TGFα in ovarian cancer cells (79). Also, resistance to TGFβ – an antiproliferative growth factor – coincides with the loss of c-MYC repression in ovarian carcinoma cells (80). On the other hand, Janicek et al. showed that PTOs against c-MYC in ovarian cancer cells leads to both antiproliferative and stimulatory activity (81).
Small Interfering RNAs (siRNAs)
SiRNA-mediated c-MYC knockdown in MYC-amplified ovarian cancer cells inhibits proliferation and induces replicative senescence by increasing the Cdk inhibitor p27 and decreasing CDK2 activity (82). High c-MYC, low p27, and high phosphorylated Rb protein signature correlates with poor patient survival in ovarian cancer (83). Induction of p27 by miR-124 decreases phosphorylated Rb and c-MYC protein levels leading to cell cycle arrest in vitro and reduced tumor growth in vivo (83). Moreover, targeting c-MYC with siRNAs in platinum-resistant ovarian cancer significantly inhibits cell growth and viability, induces cell-cycle arrest and activates apoptosis in vitro, and reduces tumor growth in vivo (67).
Small-Molecule Inhibitors
Blocking c-MYC/MAX heterodimerization with the small-molecule inhibitor 10058-F4 significantly inhibits ovarian cancer cell proliferation in part by inducing apoptosis and cell cycle arrest (84). Similarly, 10058-F4 treatment in primary cultures of epithelial ovarian carcinoma induces caspase-3 activity and inhibits cell proliferation (84). Moreover, c-MYC inhibition with 10058-F4 reduces glutamine uptake in cisplatin-resistant ovarian cancer cells (85).
Elevated expression of c-MYC has been observed in primary HGSOC cells sensitive to BRD4 inhibition by JQ1, a selective small-molecule BET bromodomain inhibitor (86). By targeting BRD4 and c-MYC, JQ1 suppresses ovarian cancer cell proliferation and induces apoptosis (87). In addition, c-MYC amplified primary cell lines and xenografts derived from chemotherapy-resistant ovarian tumors are sensitive to JQ1 (88). In fact, JQ1 increases the sensitivity of platinum-resistant ovarian cancer cells to cisplatin (87).
Dual targeting of FAK—an integrin-linked non-receptor tyrosine kinase—and c-MYC by VS-6063 and JQ1 inhibitors leads to cell cycle arrest and decreased cell survival in ovarian cancer cells in vitro (89). In primary tumors of HGSOC, co-upregulation of FAK and c-MYC suggest a co-targeting approach as a therapeutic strategy in ovarian cancer (89). Residual cells from HGSOC patients treated with neoadjuvant carboplatin and paclitaxel chemotherapy exhibit elevated FAK activity (90). Inhibiting FAK sensitizes platinum-resistant ovarian cancer tumors to cisplatin in vivo (90).
Simultaneous inhibition of CDK7 and CDK12/13 with THZ1 abrogates c-MYC expression and decreases tumor growth in platinum- and PARP inhibitor-resistant patient-derived xenograft (PDX) models of HGSOC (91). Dual inhibition of PARP (Olaparib) and CDK4/6 (Palbociclib) inhibits the growth of ovarian cancer cells in vitro and slows down tumor growth in vivo in part by inducing homologous recombination (HR) deficiency in a MYC-dependent manner (92). Concomitant upregulation of glutaminase (GLS) and c-MYC has been observed in platinum-resistant ovarian cancer cells (93). Inhibition of GLS—a downstream target of c-MYC—by CB-839 sensitizes ovarian cancer cells to PARP inhibition and prolong survival in tumor-bearing mice (93).
MicroRNAs (miRNAs)
Small non-coding RNAs such as miRNAs have been implicated as regulators and mediators of c-MYC function (37). Therefore, miRNAs may serve as potential therapeutic targets against MYC-driven cancers (37). Lower expression of miR-145 has been observed in EOC cell lines and tumor tissues, and its upregulation inhibits cell proliferation and promotes apoptosis by directly repressing c-MYC (94). In addition, miR-145 inhibits glutamine metabolism in ovarian cancer through c-MYC/GLS1 pathways (95). Furthermore, high miR-145 expression was significantly associated with increased overall survival in patients with ovarian cancer (95). Similarly, EOC tissues and cells exhibit lower levels of miR-494 (96). Overexpression of miR-494 inhibits in vitro growth and migration by directly targeting c-MYC (96). Recently, Majem et al. also found that miR-654-5p is downregulated in ovarian serous carcinomas and restoration suppresses ovarian cancer development by impacting on the oncogenic function of MYC, AKT and Wnt pathways through directly targeting CDCP1 and PLAGL2 (97).
Cisplatin-mediated downregulation of miR-145 has been shown to contribute to PD-L1 upregulation in ovarian cancer (98). Increasing miR-145 levels negatively regulates PD-L1 by repressing c-MYC expression in cisplatin-resistant ovarian cancer cells (98). These observations suggest that miR-145 may serve as an adjuvant therapeutic target in ovarian cancer (98). Sun et al. also demonstrated that c-MYC regulates cisplatin resistance in ovarian cancer by suppressing miR-137 and promoting expression of EZH2, which in turn activates cellular survival pathways (99). On the other hand, inhibition of c-MYC-miR-137 axis sensitizes resistant cells to cisplatin (99). Active c-MYC-miR-137-EZH2 was also confirmed in tumor samples from recurrent patients with ovarian cancer (99). Similarly, overexpression of let-7g increases sensitivity to cisplatin treatment in EOC, and inhibits cell growth by c-MYC and Cyclin-D2 downregulation (100). In addition, siRNA-mediated silencing of the histone deacetylase HDAC1 suppresses cell proliferation, increases apoptosis, and sensitizes ovarian cancer cells to cisplatin treatment by inducing c-MYC downregulation and miR-34a upregulation (101).
Long Non-coding RNAs (lncRNAs)
Evidence indicates that lncRNAs are able to control the expression and function of c-MYC (102). In addition, c-MYC transcriptionally regulates lncRNA expression through feedback loops (102). For example, c-MYC directly stimulates transcription of DANCR, an oncogenic lncRNA upregulated in ovarian cancer (103). Silencing DANCR increases p21 expression, decreases cell proliferation, and reduces ovarian tumor burden in an orthotopic xenograft model (103). Another oncogenic lncRNA, MALAT-1, which is upregulated in EOC tissues and cell lines, promotes c-MYC mediated epithelial-mesenchymal transition through sponging miR-22 (104). Silencing MALAT-1 inhibits cell proliferation, migration, and invasion (104). On the other hand, MAGI2-AS3, which is lowly expressed in ovarian cancer tissues and cell lines, acts as a tumor inhibitor by negatively regulating miR-525-5p and enhancing MXD1 expression (105). MXD1 competitively interacts with MAX, repressing c-MYC transcriptional activity (105). These findings suggest that targeting MYC-related lncRNAs may represent a potential alternative therapeutic strategy against ovarian cancer.
Concluding Remarks
As a transcription factor, c-MYC plays a key role in the regulation of multiple cellular processes. In non-transformed cells, c-MYC expression is tightly controlled. However, aberrant c-MYC expression has been reported in most human tumors. Thus, it is not surprising that c-MYC has been considered as a potential therapeutic target against many cancer types, including ovarian cancer. In fact, several approaches have been proposed to inhibit c-MYC either directly or indirectly, some of which have entered clinical trials. Reports on the prognostic value of c-MYC in ovarian cancer have been inconsistent, which may be explained in part by the complexity of the disease, patient background, and choice of methodology. Further investigation into the potential role of c-MYC as a prognostic marker in ovarian cancer is required in the context of histological subtypes, disease subgroups, genetic racial/ethnic differences, and reliable detection methods.
Author Contributions
JR-G and PV-M contributed to draft preparation, review, and editing. All authors contributed to the article and approved the submitted version.
Funding
This work was supported in part by the National Institute on Minority Health and Health Disparities (NIMHD) CCRHD (U54MD007600), RTRN (U54MD008149) and HCTRECD (R25MD007607), and institutional seed funds from the UPR Comprehensive Cancer Center. The funding sources had no role in writing and submitting the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. (2021) 71:7–33. doi: 10.3322/caac.21654
2. Bermejo JL, Rawal R, Hemminki K. Familial association of specific histologic types of ovarian malignancy with other malignancies. Cancer. (2004) 100:1507–14. doi: 10.1002/cncr.20138
3. Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Prim. (2016) 2:16061. doi: 10.1038/nrdp.2016.61
4. Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. (2003) 22:7265–79. doi: 10.1038/sj.onc.1206933
5. Florea A-M, Büsselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers. (2011) 3:1351–71. doi: 10.3390/cancers3011351
6. Sheiness D, Fanshier L, Bishop JM. Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol. (1978) 28:600–10. doi: 10.1128/JVI.28.2.600-610.1978
7. Mellon P, Pawson A, Bister K, Martin GS, Duesberg PH. Specific RNA sequences and gene products of MC29 avian acute leukemia virus. Proc Natl Acad Sci USA. (1978) 75:5874–8. doi: 10.1073/pnas.75.12.5874
8. Sheiness D, Bishop JM. DNA and RNA from uninfected vertebrate cells contain nucleotide sequences related to the putative transforming gene of avian myelocytomatosis virus. J Virol. (1979) 31:514–21. doi: 10.1128/JVI.31.2.514-521.1979
9. Roussel M, Saule S, Lagrou C, Rommens C, Beug H, Graf T, et al. Three new types of viral oncogene of cellular origin specific for haematopoietic cell transformation. Nature. (1979) 281:452–5. doi: 10.1038/281452a0
10. Vennstrom B, Sheiness D, Zabielski J, Bishop JM. Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J Virol. (1982) 42:773–9. doi: 10.1128/JVI.42.3.773-779.1982
11. Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA. (1982) 79:7824–7. doi: 10.1073/pnas.79.24.7824
12. Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S, et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA. (1982) 79:7837–41. doi: 10.1073/pnas.79.24.7837
13. Kohl NE, Kanda N, Schreck RR, Bruns G, Latt SA, Gilbert F, et al. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell. (1983) 35:359–67. doi: 10.1016/0092-8674(83)90169-1
14. Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F, et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature. (1983) 305:245–8. doi: 10.1038/305245a0
15. Nau MM, Brooks BJ, Battey J, Sausville E, Gazdar AF, Kirsch IR, et al. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature. (1985) 318:69–73. doi: 10.1038/318069a0
16. Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol. (2006) 16:318–30. doi: 10.1016/j.semcancer.2006.07.015
17. Massó-Vallés D, Soucek L. Blocking Myc to treat cancer: reflecting on two decades of omomyc. Cells. (2020) 9:883. doi: 10.3390/cells9040883
18. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. (2008) 8:976–90. doi: 10.1038/nrc2231
19. Whitfield JR, Beaulieu M-E, Soucek L. Strategies to inhibit Myc and their clinical applicability. Front cell Dev Biol. (2017) 5:10. doi: 10.3389/fcell.2017.00010
20. Bui T V, Mendell JT. Myc: maestro of microRNAs. Genes Cancer. (2010) 1:568–75. doi: 10.1177/1947601910377491
21. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. (2000) 100:57–70. doi: 10.1016/S0092-8674(00)81683-9
22. Gabay M, Li Y, Felsher DW. MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb Perspect Med. (2014) 4:a014241. doi: 10.1101/cshperspect.a014241
23. Torigoe T, Izumi H, Ishiguchi H, Yoshida Y, Tanabe M, Yoshida T, et al. Cisplatin resistance and transcription factors. Curr Med Chem Anticancer Agents. (2005) 5:15–27. doi: 10.2174/1568011053352587
24. Horiuchi D, Anderton B, Goga A. Taking on challenging targets: making MYC druggable. Am Soc Clin Oncol Educ Book. (2014) 34:e497–502. doi: 10.14694/EdBook_AM.2014.34.e497
25. Verdine GL, Walensky LD. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. (2007) 13:7264–70. doi: 10.1158/1078-0432.CCR-07-2184
26. Eilers M, Eisenman RN. Myc's broad reach. Genes Dev. (2008) 22:2755–66. doi: 10.1101/gad.1712408
27. Lüscher B, Larsson L-G. The basic region/helix – loop – helix/leucine zipper domain of Myc proto-oncoproteins: function and regulation. Oncogene. (1999) 18:2955–66. doi: 10.1038/sj.onc.1202750
28. Lorenzin F, Benary U, Baluapuri A, Walz S, Jung LA, von Eyss B, et al. Different promoter affinities account for specificity in MYC-dependent gene regulation. Elife. (2016) 5:e15161. doi: 10.7554/eLife.15161
29. Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan H-M, et al. MYC recruits the TIP60 histone acetyltransferase complex to chromatin. EMBO Rep. (2003) 4:575–80. doi: 10.1038/sj.embor.embor861
30. Grandori C, Cowley SM, James LP, Eisenman RN. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol. (2000) 16:653–99. doi: 10.1146/annurev.cellbio.16.1.653
31. Vervoorts J, Lüscher-Firzlaff J, Lüscher B. The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem. (2006) 281:34725–9. doi: 10.1074/jbc.R600017200
32. Frenzel A, Lovén J, Henriksson MA. Targeting MYC-Regulated miRNAs to combat cancer. Genes Cancer. (2010) 1:660–7. doi: 10.1177/1947601910377488
33. Hann SR. MYC cofactors: molecular switches controlling diverse biological outcomes. Cold Spring Harb Perspect Med. (2014) 4:a014399. doi: 10.1101/cshperspect.a014399
34. Bernasconi NL, Wormhoudt TAM, Laird-Offringa IA. Post-transcriptional deregulation of myc genes in lung cancer cell lines. Am J Respir Cell Mol Biol. (2000) 23:560–5. doi: 10.1165/ajrcmb.23.4.4233
35. Koh CM, Sabò A, Guccione E. Targeting MYC in cancer therapy: RNA processing offers new opportunities. BioEssays. (2016) 38:266–75. doi: 10.1002/bies.201500134
37. Jackstadt R, Hermeking H. MicroRNAs as regulators and mediators of c-MYC function. Biochim Biophys Acta. (2015) 1849:544–53. doi: 10.1016/j.bbagrm.2014.04.003
38. Escamilla-Powers JR, Sears RC. A conserved pathway that controls c-Myc protein stability through opposing phosphorylation events occurs in yeast. J Biol Chem. (2007) 282:5432–42. doi: 10.1074/jbc.M611437200
39. Xu J, Chen Y, Olopade OI. MYC and breast cancer. Genes Cancer. (2010) 1:629–40. doi: 10.1177/1947601910378691
40. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. (2011) 474:609–15. doi: 10.1038/nature10166
41. Yasue H, Takeda A, Ishibashi M. Amplification of the c-myc gene and the elevation of its transcripts in human ovarian tumor lines. Cell Struct Funct. (1987) 12:121–5. doi: 10.1247/csf.12.121
42. Zhou DJ, Gonzalez-Cadavid N, Ahuja H, Battifora H, Moore GE, Cline MJ. A unique pattern of proto-oncogene abnormalities in ovarian adenocarcinomas. Cancer. (1988) 62:1573–6. doi: 10.1002/1097-0142(19881015)62:8<1573::AID-CNCR2820620819>3.0.CO;2-M
43. Sasano H, Garrett CT, Wilkinson DS, Silverberg S, Comerford J, Hyde J. Protooncogene amplification and tumor ploidy in human ovarian neoplasms. Hum Pathol. (1990) 21:382–91. doi: 10.1016/0046-8177(90)90199-F
44. Liehr T, Atanasov N, Tulusan H, Gebhart E. Amplification of protooncogenes in human ovarian carcinomas. Int J Oncol. (1993) 2:155–60. doi: 10.3892/ijo.2.2.155
45. Bian M, Fan Q, Huang S, Ma J, Lang J. Amplifications of proto-oncogenes in ovarian carcinoma. Chin Med J. (1995) 108:844–8.
46. Baker VV, Borst MP, Dixon D, Hatch KD, Shingleton HM, Miller D. c-myc amplification in ovarian cancer. Gynecol Oncol. (1990) 38:340–2. doi: 10.1016/0090-8258(90)90069-W
47. Dimova I, Raitcheva S, Dimitrov R, Doganov N, Toncheva D. Correlations between c-myc gene copy-number and clinicopathological parameters of ovarian tumours. Eur J Cancer. (2006) 42:674–9. doi: 10.1016/j.ejca.2005.11.022
48. Ross JS, Ali SM, Wang K, Palmer G, Yelensky R, Lipson D, et al. Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies. Gynecol Oncol. (2013) 130:554–9. doi: 10.1016/j.ygyno.2013.06.019
49. Lee YJ, Kim D, Kim H-S, Na K, Lee J-Y, Nam EJ, et al. Integrating a next generation sequencing panel into clinical practice in ovarian cancer. Yonsei Med J. (2019) 60:914. doi: 10.3349/ymj.2019.60.10.914
50. Diebold J, Suchy B, Baretton GB, Blasenbreu S, Meier W, Schmidt M, et al. DNA ploidy and MYC DNA amplification in ovarian carcinomas. Correlation with p53 and bcl-2 expression, proliferative activity and prognosis. Virchows Arch. (1996) 429:221–7. doi: 10.1007/BF00198337
51. Wang ZR, Liu W, Smith ST, Parrish RS, Young SR. c-myc and chromosome 8 centromere studies of ovarian cancer by interphase FISH. Exp Mol Pathol. (1999) 66:140–8. doi: 10.1006/exmp.1999.2259
52. Katsaros D, Theillet C, Zola P, Louason G, Sanfilippo B, Isaia E, et al. Concurrent abnormal expression of erbB-2, myc and ras genes is associated with poor outcome of ovarian cancer patients. Anticancer Res. (1995) 15:1501–510.
53. Schreiber G, Dubeau L. C-myc proto-oncogene amplification detected by polymerase chain reaction in archival human ovarian carcinomas. Am J Pathol. (1990) 137:653–8.
54. Berns EM, Klijn JG, Henzen-Logmans SC, Rodenburg CJ, van der Burg ME, Foekens JA. Receptors for hormones and growth factors and (onco)-gene amplification in human ovarian cancer. Int J Cancer. (1992) 52:218–24. doi: 10.1002/ijc.2910520211
55. Smith DM, Groff DE, Pokul RK, Bear JL, Delgado G. Determination of cellular oncogene rearrangement or amplification in ovarian adenocarcinomas. Am J Obstet Gynecol. (1989) 161:911–5. doi: 10.1016/0002-9378(89)90750-3
56. Du ZH, Bi FF, Wang L, Yang Q. Next-generation sequencing unravels extensive genetic alteration in recurrent ovarian cancer and unique genetic changes in drug-resistant recurrent ovarian cancer. Mol Genet Genomic Med. (2018) 6:638–47. doi: 10.1002/mgg3.414
57. Yamamoto A, Kurata M, Yamamoto K, Nogawa D, Inoue M, Ishibashi S, et al. High amplification of PVT1 and MYC predict favorable prognosis in early ovarian carcinoma. Pathol Res Pract. (2020) 216:153175. doi: 10.1016/j.prp.2020.153175
58. Darcy KM, Brady WE, Blancato JK, Dickson RB, Hoskins WJ, McGuire WP, et al. Prognostic relevance of c-MYC gene amplification and polysomy for chromosome 8 in suboptimally-resected, advanced stage epithelial ovarian cancers: a Gynecologic Oncology Group study. Gynecol Oncol. (2009) 114:472–9. doi: 10.1016/j.ygyno.2009.05.012
59. Jung M, Russell AJ, Kennedy C, Gifford AJ, Mallitt K-A, Sivarajasingam S, et al. Clinical importance of Myc family oncogene aberrations in epithelial ovarian cancer. JNCI Cancer Spectr. (2018) 2:pky047. doi: 10.1093/jncics/pky047
60. Slamon DJ, deKernion JB, Verma IM, Cline MJ. Expression of cellular oncogenes in human malignancies. Science. (1984) 224:256–62. doi: 10.1126/science.6538699
61. Ning Y-X, Luo X, Xu M, Feng X, Wang J. Let-7d increases ovarian cancer cell sensitivity to a genistein analog by targeting c-Myc. Oncotarget. (2017) 8:74836–845. doi: 10.18632/oncotarget.20413
62. Kohler M, Janz I, Wintzer HO, Wagner E, Bauknecht T. The expression of EGF receptors, EGF-like factors and c-myc in ovarian and cervical carcinomas and their potential clinical significance. Anticancer Res. (1989) 9:1537–48.
63. Tashiro H, Miyazaki K, Okamura H, Iwai A, Fukumoto M. c-myc over-expression in human primary ovarian tumours: its relevance to tumour progression. Int J Cancer. (1992) 50:828–33. doi: 10.1002/ijc.2910500528
64. Bauknecht T, Angel P, Kohler M, Kommoss F, Birmelin G, Pfleiderer A, et al. Gene structure and expression analysis of the epidermal growth factor receptor, transforming growth factor-alpha, myc, jun, and metallothionein in human ovarian carcinomas classification of malignant phenotypes. Cancer. (1993) 71:419–29. doi: 10.1002/1097-0142(19930115)71:2<419::AID-CNCR2820710224>3.0.CO;2-6
65. Tanner B, Hengstler JG, Luch A, Meinert R, Kreutz E, Arand M, et al. C-myc mRNA expression in epithelial ovarian carcinomas in relation to estrogen receptor status, metastatic spread, survival time, FIGO stage, and histologic grade and type. Int J Gynecol Pathol. (1998) 17:66–74. doi: 10.1097/00004347-199801000-00012
66. Iba T, Kigawa J, Kanamori Y, Itamochi H, Oishi T, Simada M, et al. Expression of the c-myc gene as a predictor of chemotherapy response and a prognostic factor in patients with ovarian cancer. Cancer Sci. (2004) 95:418–23. doi: 10.1111/j.1349-7006.2004.tb03225.x
67. Reyes-González JM, Armaiz-Peña GN, Mangala LS, Valiyeva F, Ivan C, Pradeep S, et al. Targeting c-MYC in platinum-resistant ovarian cancer. Mol Cancer Ther. (2015) 14:2260–9. doi: 10.1158/1535-7163.MCT-14-0801
68. Skírnisdóttir IA, Sorbe B, Lindborg K, Seidal T. Prognostic impact of p53, p27, and C-MYC on clinicopathological features and outcome in early-stage (FIGO IYII) epithelial ovarian cancer. Int J Gynecol Cancer. (2011) 21:236–44. doi: 10.1097/IGC.0b013e31820986e5
69. Chen C-H, Shen J, Lee W-J, Chow S-N. Overexpression of cyclin D1 and c-Myc gene products in human primary epithelial ovarian cancer. Int J Gynecol Cancer. (2005) 15:878–83. doi: 10.1111/j.1525-1438.2005.00150.x
70. Plisiecka-Hałasa J, Karpińska G, Szymańska T, Ziółkowska I, Madry R, Timorek A, et al. P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens. Ann Oncol. (2003) 14:1078–85. doi: 10.1093/annonc/mdg299
71. van Dam PA, Vergote IB, Lowe DG, Watson J V, van Damme P, van der Auwera JC, et al. Expression of c-erbB-2, c-myc, and c-ras oncoproteins, insulin-like growth factor receptor I, and epidermal growth factor receptor in ovarian carcinoma. J Clin Pathol. (1994) 47:914–9. doi: 10.1136/jcp.47.10.914
72. Watson JV, Curling OM, Munn CF, Hudson CN. Oncogene expression in ovarian cancer: a pilot study of c-myc oncoprotein in serous papillary ovarian cancer. Gynecol Oncol. (1987) 28:137–50. doi: 10.1016/0090-8258(87)90207-1
73. Sasano H, Nagura H, Silverberg SG. Immunolocalization of c-myc oncoprotein in mucinous and serous adenocarcinomas of the ovary. Hum Pathol. (1992) 23:491–5. doi: 10.1016/0046-8177(92)90125-M
74. Li XS, Sun J, He XL. Expression of c-myc and mutation of the KRAS gene in patients with ovarian mucinous tumors. Genet Mol Res. (2015) 14:10752–9. doi: 10.4238/2015.September.9.14
75. Polacarz SV, Hey NA, Stephenson TJ, Hill AS. c-myc Oncogene product P62(c-myc) in ovarian mucinous neoplasms: Immunohistochemical study correlated with malignancy. J Clin Pathol. (1989) 42:148–52. doi: 10.1136/jcp.42.2.148
76. Curling M, Stenning S, Hudson CN, Watson JV. Multivariate analyses of DNA index, p62(c-myc), and clinicopathological status of patients with ovarian cancer. J Clin Pathol. (1998) 51:455–61. doi: 10.1136/jcp.51.6.455
77. Helm CW, Shrestha K, Thomas S, Shingleton HM, Miller DM. A unique c-myc-targeted triplex-forming oligonucleotide inhibits the growth of ovarian and cervical carcinomas in vitro. Gynecol Oncol. (1993) 49:339–43. doi: 10.1006/gyno.1993.1136
78. Fei R, Shaoyang L. Combination antigene therapy targeting c-myc and c-erbB2 in the ovarian cancer COC1 cell line. Gynecol Oncol. (2002) 85:40–4. doi: 10.1006/gyno.2001.6571
79. Park HY. Inhibition of the proliferative effect of transforming growth factor-α by c-myc antisense DNA in human ovarian cancer cells. Biochem Mol Biol Int. (1997) 43:1015–22. doi: 10.1080/15216549700204831
80. Baldwin RL, Tran H, Karlan BY. Loss of c-myc repression coincides with ovarian cancer resistance to transforming growth factor β growth arrest independent of transforming growth factor β/Smad signaling. Cancer Res. (2003) 63:1413–9.
81. Janicek MF, Sevin BU, Nguyen HN, Averette HE. Combination anti-gene therapy targeting c-myc and p53 in ovarian cancer cell lines. Gynecol Oncol. (1995) 59:87–92. doi: 10.1006/gyno.1995.1272
82. Prathapam T, Aleshin A, Guan Y, Gray JW, Martin GS. p27Kip1 mediates addiction of ovarian cancer cells to MYCC (c-MYC) and their dependence on MYC paralogs. J Biol Chem. (2010) 285:32529–38. doi: 10.1074/jbc.M110.151902
83. Seviour EG, Sehgal V, Lu Y, Luo Z, Moss T, Zhang F, et al. Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer. Oncogene. (2016) 35:691–701. doi: 10.1038/onc.2014.469
84. Wang J, Ma X, Jones HM, Chan LL-Y, Song F, Zhang W, et al. Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells. J Transl Med. (2014) 12:226. doi: 10.1186/s12967-014-0226-x
85. Hudson CD, Savadelis A, Nagaraj AB, Joseph P, Avril S, DiFeo A, et al. Altered glutamine metabolism in platinum resistant ovarian cancer. Oncotarget. (2016) 7:41637–49. doi: 10.18632/oncotarget.9317
86. Baratta MG, Schinzel AC, Zwang Y, Bandopadhayay P, Bowman-Colin C, Kutt J, et al. An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma. Proc Natl Acad Sci USA. (2015) 112:232–7. doi: 10.1073/pnas.1422165112
87. Bagratuni T, Mavrianou N, Gavalas NG, Tzannis K, Arapinis C, Liontos M, et al. JQ1 inhibits tumour growth in combination with cisplatin and suppresses JAK/STAT signalling pathway in ovarian cancer. Eur J Cancer. (2020) 126:125–35. doi: 10.1016/j.ejca.2019.11.017
88. Li C, Bonazzoli E, Bellone S, Choi J, Dong W, Menderes G, et al. Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors. Proc Natl Acad Sci USA. (2019) 116:619–24. doi: 10.1073/pnas.1814027116
89. Xu B, Lefringhouse J, Liu Z, West D, Baldwin LA, Ou C, et al. Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy. Oncogenesis. (2017) 6:e295. doi: 10.1038/oncsis.2016.86
90. Diaz Osterman CJ, Ozmadenci D, Kleinschmidt EG, Taylor KN, Barrie AM, Jiang S, et al. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy. Elife. (2019) 8:e47327. doi: 10.7554/eLife.47327
91. Zeng M, Kwiatkowski NP, Zhang T, Nabet B, Xu M, Liang Y, et al. Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13. Elife. (2018) 7:e39030. doi: 10.7554/eLife.39030
92. Yi J, Liu C, Tao Z, Wang M, Jia Y, Sang X, et al. MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer. EBioMedicine. (2019) 43:225–37. doi: 10.1016/j.ebiom.2019.03.027
93. Shen Y-A, Hong J, Asaka R, Asaka S, Hsu F-C, Suryo Rahmanto Y, et al. Inhibition of the MYC-regulated glutaminase metabolic axis is an effective synthetic lethal approach for treating chemoresistant cancers. Cancer Res. (2020) 80:4514–26. doi: 10.1158/0008-5472.CAN-19-3971
94. Zhang W, Wang Q, Yu M, Wu N, Wang H. MicroRNA-145 function as a cell growth repressor by directly targeting c-Myc in human ovarian cancer. Technol Cancer Res Treat. (2013) 13:161–8. doi: 10.7785/tcrt.2012.500367
95. Li J, Li X, Wu L, Pei M, Li H, Jiang Y. miR-145 inhibits glutamine metabolism through c-myc/GLS1 pathways in ovarian cancer cells. Cell Biol Int. (2019) 43:921–30. doi: 10.1002/cbin.11182
96. Yuan J, Wang K, Xi M. MiR-494 inhibits epithelial ovarian cancer growth by targeting c-Myc. Med Sci Monit. (2016) 22:617–24. doi: 10.12659/MSM.897288
97. Majem B, Parrilla A, Jiménez C, Suárez-Cabrera L, Barber M, Marín A, et al. MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways. Oncogene. (2019) 38:6035–50. doi: 10.1038/s41388-019-0860-0
98. Sheng Q, Zhang Y, Wang Z, Ding J, Song Y, Zhao W. Cisplatin-mediated down-regulation of miR-145 contributes to up-regulation of PD-L1 via the c-Myc transcription factor in cisplatin-resistant ovarian carcinoma cells. Clin Exp Immunol. (2020) 200:45–52. doi: 10.1111/cei.13406
99. Sun J, Cai X, Yung MM, Zhou W, Li J, Zhang Y, et al. miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer. Oncogene. (2019) 38:564–80. doi: 10.1038/s41388-018-0459-x
100. Biamonte F, Santamaria G, Sacco A, Perrone FM, Di Cello A, Battaglia AM, et al. MicroRNA let-7g acts as tumor suppressor and predictive biomarker for chemoresistance in human epithelial ovarian cancer. Sci Rep. (2019) 9:5668. doi: 10.1038/s41598-019-42221-x
101. Liu X, Yu Y, Zhang J, Lu C, Wang L, Liu P, et al. HDAC1 silencing in ovarian cancer enhances the chemotherapy response. Cell Physiol Biochem. (2018) 48:1505–18. doi: 10.1159/000492260
102. Hamilton MJ, Young MD, Sauer S, Martinez E. The interplay of long non-coding RNAs and MYC in cancer. AIMS Biophys. (2015) 2:794–809. doi: 10.3934/biophy.2015.4.794
103. Lu Y, Hu Z, Mangala LS, Stine ZE, Hu X, Jiang D, et al. MYC targeted long noncoding RNA DANCR promotes cancer in part by reducing p21 levels. Cancer Res. (2018) 78:64–74. doi: 10.1158/0008-5472.CAN-17-0815
104. Pei C, Gong X, Zhang Y. LncRNA MALAT-1 promotes growth and metastasis of epithelial ovarian cancer via sponging microrna-22. Am J Transl Res. (2020) 12:6977–87.
Keywords: ovarian cancer, MYC, undruggable oncogenes, targeted therapies, biomarkers
Citation: Reyes-González JM and Vivas-Mejía PE (2021) c-MYC and Epithelial Ovarian Cancer. Front. Oncol. 11:601512. doi: 10.3389/fonc.2021.601512
Received: 01 September 2020; Accepted: 08 February 2021;
Published: 26 February 2021.
Edited by:
Haifeng Qiu, Zhengzhou University, ChinaReviewed by:
Sophia H. L. George, University of Miami, United StatesMin Gao, Shandong University, China
Copyright © 2021 Reyes-González and Vivas-Mejía. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Pablo E. Vivas-Mejía, cGFibG8udml2YXMmI3gwMDA0MDt1cHIuZWR1