Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1–miR-593-5p–MFF axis

// Song Fan 1,2,* , Bodu Liu 1,3,* , Lijuan Sun 1,3,* , Xiao-bin Lv 1,4,* , Zhaoyu Lin 1,2,* , Weixiong Chen 2 , Weiliang Chen 2 , Qionglan Tang 5 , Youyuan Wang 2 , Yuxiong Su 6 , Shaowen Jin 7 , Daming Zhang 2 , Jianglong Zhong 2 , Yilin Li 8 , Bin Wen 9 , Zhang Zhang 10 , Pu Yang 11 , Bin Zhou 2 , Qixiang Liang 2 , Xing Yu 2 , Yinghua Zhu 4 , Pengnan Hu 3 , Junjun Chu 3 , Wei Huang 3 , Yuhuan Feng 2 , Hongzhuang Peng 12 , Qihong Huang 12 , Erwei Song 1,3 , Jinsong Li 1,2 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 2 Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 3 Department of Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 4 Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 5 Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 6 Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, the University of Hong Kong, Hong Kong 7 Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 8 Xaverian Brothers High School, Westwood, MA, USA 9 Department of Pathology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China 10 Department of Pathology, West China Hospital, Sichuan University, Chengdu, China 11 State Key Laboratory of Oral Diseases, West China Hospital, Stomatology of Sichuan University, Chengdu, China 12 The Wistar Institute, Philadelphia, PA, USA * These authors have contributed equally to this work Correspondence to: Jinsong Li, email: // Erwei Song, email: // Keywords : mitochondrial fission, cisplatin sensitivity, BRCA1, miR-593-5p, MFF Received : January 12, 2015 Accepted : February 28, 2015 Published : March 26, 2015 Abstract Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3’ untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro . The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo . Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.