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

Abstract

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.

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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). https://doi.org/10.1038/s41388-020-01443-4

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