SUV39H1 deficiency suppresses clear cell renal cell carcinoma growth by inducing ferroptosis

• 作者: Jianfeng Wang Xiaomao Yin Wei He Wei Xue Jin Zhang Yiran Huang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Original articles
• 页码范围: 406-419
• 页数: 14页
• 语种: 英文

摘要

Clear cell renal cell carcinoma(ccRCC)is a common kidney malignancy characterized by a poor prognosis.Suppressor of variegation 3-9 homolog 1(SUV39H1),which encodes a histone H3 lysine 9 methyltransferase,has been reported to act as an oncogene in many cancers.However,it is un-clear whether SUV39H1 is involved in ccRCC.Here,we report that SUV39H1 expression is frequently upregulated in ccRCC tumors and is significantly correlated with ccRCC progression.SUV39H1 expres-sion level is an independent risk factor for cancer prognosis,and integration with several known prog-nostic factors predicted ccRCC patient prognosis with improved accuracy than the conventional SSIGN(stage,size,grade and necrosis)prognostic model.Mechanistically,we discovered that siRNA knockdown or pharmacological inhibition of SUV39H1 induced iron accumulation and lipid peroxida-tion,leading to ferroptosis that disrupted ccRCC cell growth in vitro and in vivo.We also show that SUV39H1 deficiency modulated the H3K9me3 status of the DPP4(dipeptidyl-peptidase-4)gene pro-moter,resulting in upregulation of its expression that contributes to ferroptosis.Taken together,our find-ings provide the mechanistic insight into SUV39H1-dependent epigenetic control of ccRCC tumor growth and indicate that SUV39H1 may serve as a potential therapeutic target for ccRCC treatment.