TRIM24-mediated K27-linked ubiquitination of ULK1 alleviates energy stress-induced autophagy and promote prostate cancer growth in the context of SPOP mutation

Cell Death Differ. 2025 Sep 20. doi: 10.1038/s41418-025-01582-9.

Shimin Chen ^# ¹, Jichun Lin ^# ¹ ², Zhan Yang ^# ³, Yuanjing Wang ¹, Qiang Wang ², Dong Wang ¹, Yue Qu ¹, Qian Lin ¹, Jia Liu ⁴, Shi Yan ⁵, Zixin Wang ⁶, Xueyu Qian ⁶, Yutian Xiao ⁷, Xue Li ¹, Yinuo Chen ¹, Wenshuo Fang ¹, Jiaojiao Zhao ¹, Zhimin Lu ⁸ ⁹, He Ren ¹⁰ ¹¹, Yasheng Zhu ¹², Leina Ma ¹³

Affiliations

1 Department of Oncology, Cancer Institute of the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China.
2 Oncology Department, Shandong Second Provincial General Hospital, Jinan, China.
3 Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
4 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China.
5 Department of Urology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
6 College of Basic Medical Sciences, Naval Medical University, Shanghai, China.
7 Department of Urology, The First Affiliated Hospital, Naval Medical University, Shanghai, China.
8 Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. zhiminlu@zju.edu.cn.
9 Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China. zhiminlu@zju.edu.cn.
10 Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China. herenrh@163.com.
11 Gastrointestinal Cancer Institute/Pancreatic Disease Institute, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. herenrh@163.com.
12 Department of Urology, The First Affiliated Hospital, Naval Medical University, Shanghai, China. zys0562@foxmail.com.
13 Department of Oncology, Cancer Institute of the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China. leinama@gmail.com.
# Contributed equally.

PMID: 40975747 DOI: 10.1038/s41418-025-01582-9

Abstract

SPOP, the most frequently mutated gene in prostate Cancer, has been implicated in the aberrant activation of stress granules, presenting significant challenges in disease management. However, the mechanistic link between SPOP mutations and cellular energy stress remains inadequately explored. In this study, we demonstrate that ULK1 expression is positively correlated with both loss-of-function mutations in SPOP and the upregulation of the E3 ubiquitin Ligase TRIM24 in human prostate Cancer specimens. Mechanistically, SPOP mutations induce the upregulation of TRIM24, which subsequently binds to ULK1 and catalyzes its non-degradative K27-linked polyubiquitylation. This post-translational modification enhances the stability of ULK1, facilitating cellular adaptation to energy stress and consequently promoting prostate Cancer progression. Notably, pharmacological inhibition of TRIM24 using TRIM24-PROTAC (proteolysis-targeting chimera) effectively suppressed tumor growth in mice bearing SPOP-mutant prostate Cancer cells. Collectively, these findings elucidate a pivotal role of SPOP mutations in modulating energy stress responses via TRIM24-mediated ULK1 ubiquitylation and underscore the therapeutic potential of targeting TRIM24 in SPOP-mutant prostate cancers.

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