MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity


Emerging evidence indicates that myeloma overexpressed (MYEOV) is an oncogene and plays crucial roles in multiple human cancers. However, its roles in the development of pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we provide evidence of essential roles of MYEOV in the development and progression of PDAC. In tumor specimens derived from pancreatic cancer patients, MYEOV was overexpressed and associated with poor prognosis. In addition, MYEOV expression in PDAC was upregulated through promoter hypomethylation. MYEOV depletion impaired metastatic ability and proliferation of PDAC cells both in vitro and in vivo, whereas its overexpression had the opposite effect. Mechanistic investigations revealed that MYEOV interacted with SRY-Box Transcription Factor 9 (SOX9), a well-known oncogenic transcription factor in PDAC. This interaction occurred mainly in the nuclei of PDAC cells and increased transcriptional activity of SOX9. Furthermore, MYEOV promoted the expression of Hairy and enhancer of split homolog-1 (HES1), a SOX9 target gene, by enhancing SOX9 DNA-binding ability to the HES1 enhancer without affecting the protein level and subcellular localization of SOX9. HES1 knockdown partly abrogated the oncogenic effect of MYEOV. Our findings suggest that MYEOV could be a potential prognostic biomarker and therapeutic target for PDAC.

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Fig. 1: MYEOV expression is increased in PDAC and correlates with poor outcome.
Fig. 2: Promoter hypomethylation results in MYEOV overexpression.
Fig. 3: MYEOV promotes cell migration/invasion in vitro and tumor metastasis in vivo.
Fig. 4: MYEOV promotes PDAC cell proliferation in vitro and tumorigenesis in vivo.
Fig. 5: MYEOV interacts with SOX9 and increases its transactivation ability.
Fig. 6: MYEOV promotes binding of SOX9 to HES1 enhancer, and HES1 is required for MYEOV-mediated pro-metastasis function.
Fig. 7: MYEOV promotes oncogenic phenotypes of PDAC via enhancing SOX9 to transactivate HES1.


  1. 1.

    Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol. 2016;22:9694–705.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018;24:4846–61.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol. 2020;17:108–23.

  4. 4.

    Moreaux J, Hose D, Bonnefond A, Reme T, Robert N, Goldschmidt H, et al. MYEOV is a prognostic factor in multiple myeloma. Exp Hematol. 2010;38:1189–98. e3.

    CAS  PubMed  Google Scholar 

  5. 5.

    Takita J, Chen Y, Okubo J, Sanada M, Adachi M, Ohki K, et al. Aberrations of NEGR1 on 1p31 and MYEOV on 11q13 in neuroblastoma. Cancer Sci. 2011;102:1645–50.

    CAS  PubMed  Google Scholar 

  6. 6.

    Janssen JW, Imoto I, Inoue J, Shimada Y, Ueda M, Imamura M, et al. MYEOV, a gene at 11q13, is coamplified with CCND1, but epigenetically inactivated in a subset of esophageal squamous cell carcinomas. J Hum Genet. 2002;47:460–4.

    CAS  PubMed  Google Scholar 

  7. 7.

    Janssen JW, Cuny M, Orsetti B, Rodriguez C, Vallés H, Bartram CR, et al. MYEOV: a candidate gene for DNA amplification events occurring centromeric to CCND1 in breast cancer. Int J Cancer. 2002;102:608–14.

    CAS  PubMed  Google Scholar 

  8. 8.

    Horie M, Kaczkowski B, Ohshima M, Matsuzaki H, Noguchi S, Mikami Y, et al. Integrative CAGE and DNA methylation profiling identify epigenetically regulated genes in NSCLC. Mol Cancer Res. 2017;15:1354–65.

    CAS  PubMed  Google Scholar 

  9. 9.

    Fang L, Wu S, Zhu X, Cai J, Wu J, He Z, et al. MYEOV functions as an amplified competing endogenous RNA in promoting metastasis by activating TGF-β pathway in NSCLC. Oncogene. 2019;38:896–912.

    CAS  PubMed  Google Scholar 

  10. 10.

    Leyden J, Murray D, Moss A, Arumuguma M, Doyle E, McEntee G, et al. Net1 and Myeov: computationally identified mediators of gastric cancer. Br J Cancer. 2006;94:1204–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Moss AC, Lawlor G, Murray D, Tighe D, Madden SF, Mulligan AM, et al. ETV4 and Myeov knockdown impairs colon cancer cell line proliferation and invasion. Biochem Biophys Res Commun. 2006;345:216–21.

    CAS  PubMed  Google Scholar 

  12. 12.

    Harley VR, Clarkson MJ, Argentaro A. The molecular action and regulation of the testis-determining factors, SRY (sex-determining region on the Y chromosome) and SOX9 [SRY-related high-mobility group (HMG) box 9]. Endocr Rev. 2003;24:466–87.

    CAS  PubMed  Google Scholar 

  13. 13.

    Mertin S, McDowall SG, Harley VR. The DNA-binding specificity of SOX9 and other SOX proteins. Nucleic Acids Res. 1999;27:1359–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Sim H, Argentaro A, Harley VR. Boys, girls and shuttling of SRY and SOX9. Trends Endocrinol Metab. 2008;19:213–22.

    CAS  PubMed  Google Scholar 

  15. 15.

    Seymour PA, Freude KK, Tran MN, Mayes EE, Jensen J, Kist R, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA. 2007;104:1865–70.

    CAS  PubMed  Google Scholar 

  16. 16.

    Kawaguchi Y. Sox9 and programming of liver and pancreatic progenitors. J Clin Investig. 2013;123:1881–6.

    CAS  PubMed  Google Scholar 

  17. 17.

    Huang L, Holtzinger A, Jagan I, BeGora M, Lohse I, Ngai N, et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat Med. 2015;21:1364–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Sun L, Mathews LA, Cabarcas SM, Zhang X, Yang A, Zhang Y, et al. Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells. Stem Cells. 2013;31:1454–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kopp JL, von FG, Mayes E, Liu FF, Dubois CL, Morris JP, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22:737–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zhou H, Qin Y, Ji S, Ling J, Fu J, Zhuang Z, et al. SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer. Oncogene. 2018;37:912–23.

    CAS  PubMed  Google Scholar 

  21. 21.

    Grimont A, Pinho AV, Cowley MJ, Augereau C, Mawson A, Giry-Laterrière M, et al. SOX9 regulates ERBB signalling in pancreatic cancer development. Gut. 2015;64:1790–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Fukuda A, Chiba T. Sox9-dependent acinar-to-ductal reprogramming is critical for pancreatic intraepithelial neoplasia formation. Gastroenterology. 2013;145:904–7.

    PubMed  Google Scholar 

  23. 23.

    Abel EV, Kim EJ, Wu J, Hynes M, Bednar F, Proctor E, et al. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS ONE. 2014;9:e91983.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Lee JY, Song SY, Park JY. Notch pathway activation is associated with pancreatic cancer treatment failure. Pancreatology. 2014;14:48–53.

    CAS  PubMed  Google Scholar 

  25. 25.

    Nishikawa Y, Kodama Y, Shiokawa M, Matsumori T, Marui S, Kuriyama K, et al. Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis. Oncogene. 2019;38:4283–96.

    CAS  PubMed  Google Scholar 

  26. 26.

    Yen WC, Fischer MM, Axelrod F, Bond C, Cain J, Cancilla B, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 2015;21:2084–95. [PubMed: 25934888].

    CAS  PubMed  Google Scholar 

  27. 27.

    Liu ZH, Dai XM, Du B. Hes1: a key role in stemness, metastasis and multidrug resistance. Cancer Biol Ther. 2015;16:353–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Rani A, Greenlaw R, Smith RA, Galustian C. HES1 in immunity and cancer. Cytokine Growth Factor Rev. 2016;30:113–7.

    CAS  PubMed  Google Scholar 

  29. 29.

    Sato N, Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA, et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 2003;63:4158–66.

    CAS  PubMed  Google Scholar 

  30. 30.

    Mishra NK, Guda C. Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer. Oncotarget. 2017;8:28990–9012.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Huang WY, Hsu SD, Huang HY, Sun YM, Chou CH, Weng SL, et al. MethHC: a database of DNA methylation and gene expression in human cancer. Nucleic Acids Res. 2015;43:D856–61.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ruan H, Hu S, Zhang H, Du G, Li X, Li X, et al. Upregulated SOX9 expression indicates worse prognosis in solid tumors: a systematic review and meta-analysis. Oncotarget. 2017;8:113163–73.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, et al. The role of SOX family members in solid tumours and metastasis. Semin Cancer Boil. 2019;

  34. 34.

    Leung CO, Mak WN, Kai AK, Chan KS, Lee TK, Ng IO, et al. Sox9 confers stemness properties in hepatocellular carcinoma through Frizzled-7 mediated Wnt/β-catenin signaling. Oncotarget. 2016;7:29371–86.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Shen Z, Deng H, Fang Y, Zhu X, Ye GT, Yan L, et al. Identification of the interplay between SOX9 and S100P in the metastasis and invasion of colon carcinoma. Oncotarget. 2015;6:20672–84.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Shi J, Guo J, Li X. Role of LASP-1, a novel SOX9 transcriptional target, in the progression of lung cancer. Int J Oncol. 2018;52:179–88.

    CAS  PubMed  Google Scholar 

  37. 37.

    Li T, Huang H, Shi G, Zhao L, Li T, Zhang Z, et al. TGF-β1-SOX9 axis-inducible COL10A1 promotes invasion and metastasis in gastric cancer via epithelial-to-mesenchymal transition. Cell Death Dis. 2018;9:849.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Müller P, Crofts JD, Newman BS, Bridgewater LC, Lin CY, Gustafsson JA, et al. SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells. Breast Cancer Res Treat. 2010;120:317–26.

    PubMed  Google Scholar 

  39. 39.

    Janssen JW, Vaandrager JW, Heuser T, Jauch A, Kluin PM, Geelen E, et al. Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32). Blood. 2000;95:2691–8.

    CAS  PubMed  Google Scholar 

  40. 40.

    Coccaro N, Tota G, Anelli L, Zagaria A, Casieri P, Cellamare A, et al. MYEOV gene overexpression in primary plasma cell leukemia with t(11;14)(q13;q32). Oncol Lett. 2016;12:1460–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lawlor G, Doran PP, MacMathuna P, Murray DW. MYEOV (myeloma overexpressed gene) drives colon cancer cell migration and is regulated by PGE2. J Exp Clin Cancer Res. 2010;29:81.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Xie VK, Li Z, Yan Y, Jia Z, Zuo X, Ju Z, et al. DNA-Methyltransferase 1 induces dedifferentiation of pancreatic cancer cells through silencing of Krüppel-Like Factor 4 expression. Clin Cancer Res. 2017;23:5585–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Zhao T, Jiang W, Wang X, Wang H, Zheng C, Li Y, et al. ESE3 inhibits pancreatic cancer metastasis by upregulating E-Cadherin. Cancer Res. 2017;77:874–85.

    CAS  PubMed  Google Scholar 

  44. 44.

    Royo JL, Hidalgo M, Ruiz A. Pyrosequencing protocol using a universal biotinylated primer for mutation detection and SNP genotyping. Nat Protoc. 2007;2:1734–9.

    CAS  PubMed  Google Scholar 

  45. 45.

    Deng F, Peng L, Li Z, Tan G, Liang E, Chen S, et al. YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury. Cell Death Dis. 2018;9:153.

    PubMed  PubMed Central  Google Scholar 

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Correspondence to Fachao Zhi.

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Liang, E., Lu, Y., Shi, Y. et al. MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity. Oncogene 39, 6437–6450 (2020).

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