Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.

Autor: Johnson M; Department of Chemistry and Biochemistry, Université de Moncton, Canada.; Atlantic Cancer Research Institute, Moncton, Canada., Turcotte S; Department of Chemistry and Biochemistry, Université de Moncton, Canada.; Atlantic Cancer Research Institute, Moncton, Canada.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2024 Nov 26. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1002/1878-0261.13770
Abstrakt: Loss of chromosome 3p and loss of heterogeneity of the von Hippel-Lindau (VHL) gene are common characteristics of clear cell renal cell carcinoma (ccRCC). Despite frequent mutations on VHL, a fraction of tumors still grows with the expression of wild-type (WT) VHL and evolve into an aggressive subtype. Additionally, mutations on chromatin-modifying genes, such as the gene coding for the histone methyltransferase SET containing domain 2 (SETD2), are essential to ccRCC evolution. We previously identified STF-62247, a small molecule first discovered as a synthetically lethal molecule for VHL-deficient cells by blocking late stages of autophagy. This study investigated how other commonly mutated genes in ccRCC could impact the response to STF-62247. We showed that SETD2 inactivation in ccRCC cells expressing WT-VHL became vulnerable to STF-62247, as indicated by decreases in cell proliferation and survival. Furthermore, activation of the DNA damage response pathway leads to the loss of M-phase inducer phosphatase 1 (CDC25A) and cell cycle arrest in S phase. Cleavage of both caspase-3 and gasdermin E suggests that STF-62247 eliminates WT-VHL ccRCC cells through pyroptosis specifically when SETD2 is inactivated.
(© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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