In prostate cancer, the development of resistance to androgen receptor (AR)-targeted therapies (ATTs) and chemotherapies is associated with the emergence of new phenotypic states with altered molecular features. Here, we identify ubiquitin-specific peptidase 2 (USP2) as a mediator of this phenomenon. USP2 is induced in response to ATTs and more highly expressed in aggressive, castration-resistant prostate tumours that have lost dependence on AR as an oncogenic driver. Overexpression of USP2 in prostate cancer cells elicited elevated rates of glycolysis, neuroendocrine features and resistance to docetaxel, an important chemotherapeutic agent for advanced prostate cancer. USP2 stabilised key oncoproteins, including Aurora kinase A, cyclin D1 and fatty acid synthase. An unbiased proteomic approach identified potential new USP2 substrates and a USP2-regulated proteome that is associated with metastatic disease. Genetic or pharmacological targeting of USP2 caused cell death in human and mouse models of aggressive prostate cancer and the USP2 inhibitor ML364 exhibited potent anti-tumour effects against an orthotopic xenograft model of AR-null disease. Collectively, this study identifies USP2 as a critical regulator of proteins involved in prostate cancer progression and therapy resistance, positioning it as a viable therapeutic target.
Cell death & disease. 2026 Jun 02 [Epub ahead of print]
Danielle Meiwen Fang, Raj K Shrestha, Beatriz German, Razia Rahman, Scott L Townley, Jianling Xie, Adrienne R Hanson, Richard Iggo, Zeyad D Nassar, Madison Helm, Shashikanth Marri, Alex D Colella, Giles Best, Margaret M Centenera, Wayne D Tilley, Tim K Chataway, Leigh Ellis, Lisa M Butler, Luke A Selth
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia., Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia. .