A Methylation-Based Regulatory Network for MicroRNA 320a in Chemoresistant Breast Cancer

• DOI: 10.1124/mol.114.092759
• Publication Date: 2014-08-27T06:35:04Z
• Authors: Dong-Xu He; Xiao-Ting Gu; Li Jiang; Jian Jin; Xin Ma
• Keywords: 0301 basic medicine; NFATC Transcription Factors; Down-Regulation; Breast Neoplasms; Methylation; 3. Good health; Proto-Oncogene Protein c-ets-1; MicroRNAs; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; MCF-7 Cells; Humans; Female; Gene Regulatory Networks; Promoter Regions, Genetic; TRPC Cation Channels

We previously demonstrated that the overexpression of transient receptor potential channel C5 (TRPC5) and nuclear factor of activated T-cells isoform c3 (NFATC3) are essential for cancer chemoresistance, but how TRPC5 and NFATC3 are regulated was still unclear. In this study, microRNA 320a (miR-320a) was found to be down-regulated in chemoresistant cancer cells. MiR-320a directly targeted TRPC5 and NFATC3, and down-regulation of miR-320a triggered TRPC5 and NFATC3 overexpression. In chemoresistant cells, down-regulation of miR-320a was associated with regulation by methylation, which implicated promoter methylation of the miR-320a coding sequence. Furthermore, the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1), which inhibited miR-320a expression, was activated in chemoresistant cancer cells; such activation was associated with hypomethylation of the ETS-1 promoter. Lastly, the down-regulation of miR-320a and high expression of TRPC5, NFATC3, and ETS-1 were verified in clinically chemoresistant samples. Low expression of MiR-320a was also found to be a significant unfavorable predictor for clinic outcome. In conclusion, miR-320a is a mediator of chemoresistance by targeting TRPC5 and NFATC3. Expression of miR-320a is regulated by methylation of its promoter and that of ETS-1.