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Genome-wide CRISPR/Cas9 screening identifies PTGR2 as a potential therapeutic target for sunitinib resistance in clear cell renal cell carcinoma
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Genome-wide CRISPR/Cas9 screening identifies PTGR2 as a potential therapeutic target for sunitinib resistance in clear cell renal cell carcinoma
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Genome-wide CRISPR/Cas9 screening identifies PTGR2 as a potential therapeutic target for sunitinib resistance in clear cell renal cell carcinoma
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Journal Article
Genome-wide CRISPR/Cas9 screening identifies PTGR2 as a potential therapeutic target for sunitinib resistance in clear cell renal cell carcinoma
2025
Overview
Acquired and intrinsic resistance to sunitinib is a major obstacle to improving the therapeutic efficacy of treatment for clear cell renal cell carcinoma (ccRCC). This study aimed to identify novel therapeutic targets and the potential molecular mechanisms to overcome sunitinib resistance in ccRCC. Utilizing genome-wide CRISPR/Cas9 screening and resistant transcriptomics, we identified that prostaglandin reductase 2 (PTGR2) is a novel therapeutic target to overcome sunitinib resistance in ccRCC. The silencing of PTGR2 enhanced the cytotoxic effects of sunitinib in ccRCC cells, as measured by cell viability assays, and suppressed tumor growth in xenograft models. Mechanistically, PTGR2 physically interacts with lysine specific demethylase 6A (KDM6A) via endogenous/exogenous co-immunoprecipitation. PTGR2 knockdown reduced KDM6A protein expression, while KDM6A overexpression partially reversed the sensitization effect of PTGR2 silencing, suggesting KDM6A is a major downstream effector. Our findings establish the PTGR2-KDM6A axis as a potential target for overcoming sunitinib resistance in ccRCC. Pharmacological inhibition of PTGR2 or targeted modulation of KDM6A activity represents a promising combination strategy to overcome sunitinib resistance and improve patient outcomes.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Animals
/ Antineoplastic Agents - pharmacology
/ Carcinoma, Renal Cell - drug therapy
/ Carcinoma, Renal Cell - genetics
/ Carcinoma, Renal Cell - metabolism
/ Carcinoma, Renal Cell - pathology
/ Clear cell-type renal cell carcinoma
/ CRISPR
/ Drug Resistance, Neoplasm - genetics
/ Gene Expression Regulation, Neoplastic - drug effects
/ Genes
/ Genome-wide CRISPR/Cas9 screening
/ Genomes
/ Histone Demethylases - genetics
/ Histone Demethylases - metabolism
/ Humanities and Social Sciences
/ Humans
/ KDM6A
/ Kidney Neoplasms - drug therapy
/ Kidney Neoplasms - metabolism
/ Kidney Neoplasms - pathology
/ Kinases
/ Mice
/ Proteins
/ PTGR2
/ Science
