An RNA Helicase DHX33 Inhibitor Shows Broad Anticancer Activity via Inducing Ferroptosis in Cancer Cells.

RNA helicase DHX33 has been identified as a critical factor promoting cancer development. In the present study, a previously developed small molecule inhibitor for DHX33, KY386, was found to robustly kill cancer cells via a new path, the ferroptosis pathway. Mechanistically, DHX33 promotes the expression of critical players in lipid metabolism including FADS1, FADS2, and SCD1 genes, thereby sensitizing cancer cells to ferroptosis mediated cell death. Our study reveals a novel mechanism of DHX33 in promoting tumorigenesis and highlights that pharmacological targeting DHX33 can be a feasible option in human cancers. Normally differentiated cells are insensitive to DHX33 inhibition, and DHX33 inhibitors have little cellular toxicity in vitro and in vivo. Our studies demonstrated that DHX33 inhibitors can be promising anticancer agents with great potential for cancer treatment.

DHX33 mediates p53 to regulate mevalonate pathway gene transcription in human cancers.

Tumor suppressor p53 is frequently null or mutated in human cancers. Here in this study, DHX33 protein was found to be induced in p53 null cells in vitro, and in p53 mutant lung tumorigenesis in vivo. Cholesterol metabolism through mevalonate pathway is pivotal for cell proliferation and is frequently altered in human cancers. Mice carrying mutant p53 and KrasG12D alleles showed upregulation of mevalonate pathway gene expression. However upon DHX33 loss, their upregulation was significantly debilitated. Additionally, in many human cancer cells, DHX33 knockdown caused inhibition of mavelonate pathway gene transcription. We propose DHX33 locates downstream of mutant p53 and Ras to regulate mevalonate pathway gene transcription and thereby supports cancer development in vivo.