Theranostics 2017; 7(13):3293-3305. doi:10.7150/thno.19988
EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes
1. Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008 China;
2. Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078 China;
3. Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, China;
4. Institute of Medical Sciences, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008 China;
5. Department of Pathology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008 China;
6. Shanghai Institute of Material Medica, Chinese Academy of Sciences (CAS), 555 Zu Chongzhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China;
7. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078 China;
8. Department of Pathology, Yale School of Medicine, New Haven, CT, 06520 U.S.A.
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.
Keywords: Ferroptosis, LSH, WDR76, EGLN1, PHD2, c-Myc, HIF-1α, SCD1, FADS2, Iron, Lipid reactive oxygen species, Metabolism, Lung cancer.
Jiang Y, Mao C, Yang R, Yan B, Shi Y, Liu X, Lai W, Liu Y, Wang X, Xiao D, Zhou H, Cheng Y, Yu F, Cao Y, Liu S, Yan Q, Tao Y. EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes. Theranostics 2017; 7(13):3293-3305. doi:10.7150/thno.19988. Available from http://www.thno.org/v07p3293.htm