Loss of UFL1 drives chromosome instability and tumorigenesis of prostate cancer

• 成果类型: Article
• 署名作者: Li, Jimin; Yang, Fang; Zhang, Xiao; Xu, Liangfei; Zheng, Hui; Liu, Liu; Wan, Xin; Xu, Tao; Jiang, Guanmin; Wang, Hao
• 署名单位: Chinese Academy of Sciences; University of Science & Technology of China, CAS; Wannan Medical University; Chinese People's Liberation Army General Hospital; Anhui Medical University; Sun Yat Sen University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2523965123
• 发表日期: 2026-04-20
• 页码: e2523965123
• 关键词: prostate cancer; chromosomal instability; UFL1; RNF20; histone h2b; dna-damage; aneuploidy; transcription; centrosome; MONOUBIQUITYLATION; monoubiquitination; phosphorylation; ubiquitination; resistance

摘要

Chromosomal instability (CIN) is a prevalent form of genomic instability in prostate cancer (PCa). However, its molecular mechanisms remain inadequately understood. This study demonstrates that reduced expression of UFM1-ligase 1 (UFL1) is commonly observed in PCa and correlates with elevated CIN rates. UFL1 deficiency results in severe mitotic defects, errors in chromosome segregation, and aneuploidy, thereby promoting malignant transformation. Mechanistically, UFL1 interacts with RNF20 and catalyzes its UFMylation, which enhances RNF20 binding to CEP192, facilitating its centrosomal localization and supporting mitotic spindle assembly. Additionally, downregulation of the microphthalmia-associated transcription factor (MITF) exacerbates PCa aggressiveness by suppressing UFL1 expression. These findings identify the MITF-UFL1-RNF20 axis as a critical regulator of spindle integrity and a potential therapeutic target in PCa.