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miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer

Oncogene volume 38, pages 564–580 (2019)Cite this article

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Abstract

Platinum drugs are used in first-line to treat ovarian cancer, but most of the patients eventually generate resistance after treatment with these drugs. Although both c-Myc and EZH2 have been implicated in regulating cisplatin resistance in ovarian cancer, the interplay between these two regulators is poorly understood. Using RNA sequence analysis (RNA-seq), for the first time we find that miR-137 level is extremely low in cisplatin resistant ovarian cancer cells, correlating with higher levels of c-Myc and EZH2 expression. Further analyses indicate that in resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin. Inhibition of c-Myc-miR-137-EZH2 pathway re-sensitizes resistant cells to cisplatin. Both in vivo and in vitro analyses indicate that cisplatin treatment activates c-Myc-miR-137-EZH2 pathway. Importantly, elevated c-Myc-miR-137-EZH2 pathway in resistant cells is sustained by dual oxidase maturation factor 1 (DUOXA1)-mediated production of reactive oxygen species (ROS). Significantly, clinical studies further confirm the activated c-Myc-miR-137-EZH2 pathway in platinum drug-resistant or recurrent ovarian cancer patients. Thus, our studies elucidate a novel role of miR-137 in regulating c-Myc-EZH2 axis that is crucial to the regulation of cisplatin resistance in ovarian cancer.

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Acknowledgements

This work was partially supported by funding from the National Institutes of Health (CA177898 and CA184717 to WZ), the McCormick Genomic and Proteomic Center. W. Zhu was supported by a Research Scholar Grant, RSG-13-214-01-DMC from the American Cancer Society.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Jing Sun, Xin Cai, Wei Zhou, Jing Li, Yi Zhang, Zhuqing Li & Wenge Zhu

  2. GW Cancer Center, The George Washington University, Washington, DC, 20052, USA

    Jing Sun, Xin Cai, Wei Zhou, Jing Li, Yi Zhang, Zhuqing Li, Yan Kai, Alexandros Tzatsos & Wenge Zhu

  3. Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Mingo MH Yung, Stephanie S. Liu, Hextan Y. S. Ngan & David W. Chan

  4. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Wei Zhou

  5. Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Annie N. Y. Cheung

  6. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China

    Yiliang Li

  7. Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, China

    Zhijun Dai

  8. Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA

    Yan Kai & Weiqun Peng

  9. Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Alexandros Tzatsos

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Sun, J., Cai, X., Yung, M.M. et al. miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer. Oncogene 38, 564–580 (2019). https://doi.org/10.1038/s41388-018-0459-x

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