N6-methyladenosine-modified RNF220 induces cisplatin resistance and immune escape via regulating PDE10A K48-linked ubiquitination in bladder cancer

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-03-28 DOI:10.1016/j.bcp.2025.116903

Kai Li , Yongshan Li , Yetao Zhang , Jiancheng Lv , Tong Zhao , Yuxiang Dong , Fuyang Liu , Jun Wang , Yong Wei , Qingyi Zhu

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Abstract

Bladder cancer (BCa) remains one of the most prevalent malignancies worldwide, with cisplatin-based combination chemotherapy as the cornerstone of adjuvant treatment. However, cisplatin resistance frequently arises in advanced BCa, limiting therapeutic efficacy. Comparative proteomic analysis of cisplatin-sensitive and -resistant BCa cells identified phosphodiesterase 10A (PDE10A) as significantly downregulated at the protein level in resistant cells, despite unchanged mRNA levels, indicating post-transcriptional regulation. Functional assays demonstrated that PDE10A enhanced cisplatin sensitivity by promoting apoptosis. Mechanistically, the E3 ubiquitin ligase RNF220 directly interacted with PDE10A, facilitating its ubiquitination and degradation under cisplatin-resistant conditions. RNF220 overexpression markedly reinforced cisplatin resistance in vitro and in vivo. Furthermore, N6-methyladenosine (m6A) modification mediated by METTL3 stabilized RNF220 mRNA in an IGF2BP2-dependent manner. Additionally, RNF220 promoted PD-L1 expression by destabilizing PDE10A, thereby facilitating immune evasion in BCa. These findings establish RNF220 as a pivotal ubiquitinase that drives both cisplatin resistance and immune escape through PDE10A destabilization, highlighting its potential as a therapeutic target to enhance chemotherapy and immunotherapy efficacy in advanced BCa.

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.