ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression [RNA-Seq]

Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.