Objectives: Cisplatin resistance is a major obstacle in the treatment of renal cell carcinoma (RCC), severely compromising therapeutic efficacy and patient prognosis. This study aimed to clarify the role and molecular mechanism of cyclin-dependent kinase 4 (CDK4) in cisplatin resistance of RCC. Methods: Immunohistochemistry (IHC) was used to detect the expression of CDK4 in cisplatin-resistant RCC tissues. In RCC cells and their drug-resistant sublines, CDK4 overexpression/knockdown assays were performed to evaluate the effects on cisplatin resistance and malignant progression. An in vivo model was established, to verify the in vivo function of CDK4. Transcriptome sequencing (RNA-seq), Cleavage Under Targets and Tagmentation (CUT by upregulating ASH1L, CDK4 inhibited the expression of copper transporter 1 (CTR1), thereby mediating cisplatin resistance. Targeted inhibition of CDK4 or ASH1L enhanced the cisplatin sensitivity of RCC cells. Conclusions: This study identifies the critical role of the CDK4-ASH1L-CTR1 axis in cisplatin resistance of RCC.
Zeng et al. (Thu,) studied this question.