TET2 deficiency sensitizes tumor cells to statins by reducing HMGCS1 expression
作者全名："Sun, Si-Jia; Ai, Ying-Jie; Duan, Kun-Long; Zhang, Jin-Ye; Zhang, Cheng; Sun, Yi-Ping; Xiong, Yue; Guan, Kun-Liang; Yuan, Hai-Xin"
作者地址："[Sun, Si-Jia; Duan, Kun-Long; Zhang, Jin-Ye; Zhang, Cheng; Sun, Yi-Ping; Yuan, Hai-Xin] Fudan Univ, Shanghai Coll Med, Peoples Hosp Shanghai 5, Inst Biomed Sci,Mol & Cell Biol Res Lab, Shanghai, Peoples R China; [Ai, Ying-Jie] Fudan Univ, Zhongshan Hosp, Shanghai Coll Med, Dept Gastroenterol & Hepatol, Shanghai, Peoples R China; [Xiong, Yue] Cullgen Inc, 12730 High Bluff Dr, San Diego, CA 92130 USA; [Guan, Kun-Liang] Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92093 USA; [Guan, Kun-Liang] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92093 USA; [Yuan, Hai-Xin] Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China"
通信作者："Yuan, HX (通讯作者)，Fudan Univ, Shanghai Coll Med, Peoples Hosp Shanghai 5, Inst Biomed Sci,Mol & Cell Biol Res Lab, Shanghai, Peoples R China.; Yuan, HX (通讯作者)，Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China."
ESI学科分类：MOLECULAR BIOLOGY & GENETICS
文献类型：Article; Early Access
摘要："TET2 (ten-eleven-translocation) protein is a Fe(II)- and alpha-ketoglutarate-dependent dioxygenase that catalyzes DNA demethylation to regulate gene expression. While TET2 gene is frequently mutated in hematological cancer, its enzymatic activity is also compromised in various solid tumors. Whether TET2 deficiency creates vulnerability for cancer cells has not been studied. Here we reported that TET2 deficiency is associated with the change of lipid metabolism processes in acute myeloid leukemia (AML) patient. We demonstrate that statins, the inhibitors of beta-Hydroxy beta-methylglutaryl-CoA (HMG-CoA) reductase and commonly used cholesterol-lowering medicines, significantly sensitize TET2 deficient tumor cells to apoptosis. TET2 directly regulates the expression of HMG-CoA synthase (HMGCS1) by catalyzing demethylation on its promoter region, and conversely TET2 deficiency leads to significant down-regulation of HMGCS1 expression and the mevalonate pathway. Consistently, overexpression of HMGCS1 in TET2-deficient cells rescues statin-induced apoptosis. We further reveal that decrease of geranylgeranyl diphosphate (GGPP), an intermediate metabolite in the mevalonate pathway, is responsible for statin-induced apoptosis. GGPP shortage abolishes normal membrane localization and function of multiple small GTPases, leading to cell dysfunction. Collectively, our study reveals a vulnerability in TET2 deficient tumor and a potential therapeutic strategy using an already approved safe medicine."
基金机构：National Key Research and Development Project of China [2018YFA0800304]; NSFC ; Development Fund for Shanghai Talents ; Supporting Fund for Innovation and Entrepreneurship by Chongqing Returned Oversea Scholars
基金资助正文："This work was supported by the National Key Research and Development Project of China (No. 2018YFA0800304 to H.-X.Y.), the NSFC grants (No. 82172595 to H.-X.Y.), and the Development Fund for Shanghai Talents (No. 2019109 to H.-X.Y.). H.-X.Y. is also supported by the Supporting Fund for Innovation and Entrepreneurship by Chongqing Returned Oversea Scholars."