EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes

Release time:2020-07-13

Impact Factor:8.579

Affiliation of Author(s):中南大学

Journal:Theranostics

Key Words:EGLN1; FADS2; Ferroptosis; HIF-1α; Iron; LSH; Lipid reactive oxygen species; Lung cancer.; Metabolism; PHD2; SCD1; WDR76; c-Myc.

Abstract:Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.

Co-author:Chao Mao, Rui Yang, Bin Yan, Ying Shi, Xiaoli Liu, Weiwei Lai, Yating Liu, Xiang Wang, Desheng Xiao, Hu Zhou, Yan Cheng, Fenglei Yu, Ya Cao, Shuang Liu, Qin Yan

First Author:Yiqun Jiang

Indexed by:Journal paper

Correspondence Author:Yongguang Tao

Volume:7(13)

Page Number:3293-3305

Translation or Not:no

Date of Publication:2017-07-23

Included Journals:SCI