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Knockdown of SETD2 promotes erastin-induced ferroptosis in ccRCC
Wei Xue1, Wengang Jian1, Yuyang Meng1
1Department of Urology, the First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
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.
Insights
Low levels of SETD2 epigenetic molecule correlate with poor prognosis in clear cell renal cell carcinoma (ccRCC). Knockdown of SETD2 enhances ferroptosis sensitivity, suggesting SETD2 as a potential therapeutic target for ccRCC.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype with a poor prognosis.
- SET-domain-containing 2 (SETD2), a histone methyltransferase, is often underexpressed and mutated in ccRCC.
- Ferroptosis, a distinct cell death pathway, has been observed in renal cancer, but its link to SETD2 is unclear.
Purpose of the Study:
- To investigate the relationship between SETD2 expression and ferroptosis in ccRCC.
- To elucidate the underlying molecular mechanisms connecting SETD2, histone modification, and ferroptosis.
- To evaluate SETD2 as a potential therapeutic target in ccRCC.
Main Methods:
- Assessed SETD2 expression levels in ccRCC tissues and correlated with prognosis.
- Performed SETD2 knockdown experiments in tumor cells.
- Measured lipid peroxidation and Fe2+ levels.
- Investigated the interaction between SETD2-catalyzed H3K36me3 and the ferrochelatase (FECH) promoter.
- Analyzed ferroptosis-related signaling pathways.
Main Results:
- SETD2 expression was low in ccRCC and associated with poor prognosis.
- SETD2 knockdown increased tumor cell lipid peroxidation and Fe2+ levels.
- Reduced SETD2 enhanced sensitivity to erastin, a ferroptosis inducer.
- SETD2-mediated H3K36 trimethylation regulates FECH transcription and ferroptosis pathways.
Conclusions:
- SETD2 downregulation promotes ferroptosis sensitivity in ccRCC.
- Targeting SETD2 may enhance the efficacy of ferroptosis inducers for ccRCC treatment.
- SETD2 represents a potential therapeutic target for improving ccRCC outcomes.
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