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

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.

Long non‐coding RNA linc01433 promotes migration and invasion in non‐small cell lung cancer

“…Linc01433 is thus a cancer‐related lncRNA that may have an oncogene‐like effect on NSCLC. As chromatin modifiers and metabolism are involve in tumorigenicity, and the interplay of lncRNAs on metabolism is regarded as a hallmark of cancer, it will be interesting to determine whether linc01433 could regulate other possible metabolic targets and the potential mechanisms.…”

“…Although substantial research of lung‐cancer‐related lncRNAs has been conducted, no lncRNA that can serve as a single molecular marker to diagnose lung cancer has been identified, therefore we need to explore other lncRNAs to obtain a better understanding of this disease. In our previous study, we focused on one of the genes with a change in expression between tumor tissues and matched normal lung tissues, determined by RNA‐sequencing . Specifically, we found that the linc01433 expression level was significantly higher in tumor tissues, suggesting that it may be a novel prognostic factor for human NSCLC.…”

The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis

“…Demethylation, in contrast, has the opposite effect. Of note, some chromatic remodeling factors, including lymphoid-specific helicase (LSH), have been validated to play pivotal roles in the tumor progression and prognosis of multiple cancers, including gliomas [75,76], lung cancer [77][78][79] and nasopharyngeal carcinoma [80].…”

The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

“…Lymphocyte-specific helicase (LSH), a member of the ATP-dependent helicase in sucrose nonfermenting 2 (SNF2), plays an important role in normal cell development, metabolism and cancer progression [79,87,[118][119][120][121][122][123][124][125][126][127][128][129]. Interestingly, LSH inhibits ferroptosis and promotes lung tumorigenesis by affecting metabolic genes through chromatin modification [119]. LSH contributes to the recruitment of the WD repeat domain 76 (WDR76) to the metabolic gene promoters, including stearoyl-CoA desaturase 1(SCD1) and fatty acid desaturases 2 (FADS2).…”