Abstract 1474: Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism

Abstract

Abstract Cancer cells amplify the expression of ASC amino acid transporter 2 (ASCT2, also called SLC1A5), a high-affinity glutamine carrier protein, to coordinate metabolic reprogramming and malignant transformation. Yet genetic and/or epigenetic mechanisms underlying the control of ASCT2-mediated glutamine metabolism remain to be clarified. Combined in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor miR-137 as an essential regulator that targets ASCT2 mRNA and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and its decreased transcription, which conversely enhances ASCT2 expression and glutamine metabolism. As such, expression between miR-137 and ASCT2 is inversely correlated in multiple human cancer types, including colorectal carcinomas, glioblastomas, prostate and pancreatic cancers. These findings thus elucidate a universal mechanism responsible for ASCT2 deregulation in human cancers, revealing a molecular link between miR-137, ASCT2 and tumor metabolism. Citation Format: Xiao Daibiao, Junli Dong, Zihan Zhao, Ping Ren, Cong Li, Yufeng Hu, Jianguo Shi, Hexiu Su, Zhaojing Wang, Hudan Liu, Bo Li, Peng Gao, Guoliang Qing. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1474. doi:10.1158/1538-7445.AM2017-1474