1. Academic Validation
  2. Knockdown of SETD2 promotes erastin-induced ferroptosis in ccRCC

Knockdown of SETD2 promotes erastin-induced ferroptosis in ccRCC

  • Cell Death Dis. 2023 Aug 21;14(8):539. doi: 10.1038/s41419-023-06057-8.
Wei Xue # 1 Wengang Jian # 1 Yuyang Meng 1 Tengda Wang 1 Licheng Cai 1 Yongchun Yu 1 Yipeng Yu 1 Zhinan Xia 1 Cheng Zhang 2 3
Affiliations

Affiliations

  • 1 Department of Urology, the First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
  • 2 Department of Urology, the First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China. zhangcheng13836182568@zju.edu.cn.
  • 3 Department of Urology, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, China. zhangcheng13836182568@zju.edu.cn.
  • # Contributed equally.
Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney Cancer and is associated with poor prognosis. The histone H3 lysine 36 methyltransferase SET-domain-containing 2 (SETD2) has been reported to be expressed at low levels and frequently mutated in ccRCC. Ferroptosis, a form of death distinct from Apoptosis and necrosis, has been reported in recent years in renal Cancer. However, the relationship between SETD2 and Ferroptosis in renal Cancer is not clear. Here, we demonstrated that SETD2 was expressed at low levels in ccRCC and was associated with poor prognosis. Moreover, we found that knockdown of SETD2 increased lipid peroxidation and Fe2+ levels in tumor cells, thereby increasing the sensitivity of erastin, a Ferroptosis inducer. Mechanistically, histone H3 lysine 36 trimethylation (H3K36me3) which was catalyzed by SETD2, interacted with the promoter of ferrochelatase (FECH) to regulate its transcription and ferroptosis-related signaling pathways. In conclusion, the presesnt study revealed that knockdown of the epigenetic molecule, SETD2, significantly increases the sensitivity of Ferroptosis inducers which promotes tumor cell death, thereby indicating that SETD2 may be a potential therapeutic target for ccRCC.

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