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

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.

Panax notoginseng saponins radiosensitize colorectal cancer cells by regulating the SNHG6/miR-137 axis

“…[31][32][33] Additionally, miR-137 enhanced the chemosensitivity in ovarian cancer and colon cancer. 34,35 In the present study, we rstly validated that SNHG6 directly targeted miR-137 and repressed miR-137 expression. Moreover, miR-137 mediated the regulatory effect of SNHG6 on radiosensitivity in CRC cells.…”

miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4

“…miR-137 hypermethylation leads to its inhibition in many tumors, such as colorectal cancer, pancreatic cancer, and endometrial cancer [29][30][31] . Functional analysis has indicated that miR-137 can inhibit cell proliferation, cell cycle arrest and apoptosis, cell migration and invasion, and affect chemoresistance [32][33][34][35][36] . For example, miR-137 overexpression sensitized resistant colon cancer cells to oxaliplatin 20 .…”

Long non-coding RNA CASC9 promotes gefitinib resistance in NSCLC by epigenetic repression of DUSP1

“…EZH2 is involved in treatment resistance in multiple cancers. For example, EZH2 epigenetically regulates the FADD/PARP1 axis, leading to TMZ resistance in glioma 33 ; EZH2 activates cellular survival pathways, resulting in resistance to cisplatin 34 ; and H3K27 mediated by EZH2 induces multidrug resistance in small cell lung cancer 35 . In the present study, EZH2 knockdown partially reversed gefitinib resistance, inhibited cell proliferation, and induced apoptosis in PC9/GR cells.…”