USP2 is an androgen-repressed survival factor that stabilises oncoproteins to facilitate therapy resistance in prostate cancer

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. Over-expression of USP2 in prostate cancer cells elicited elevated rates of glycolysis, neuroendocrine features and resistance to docetaxel, a taxane chemotherapeutic that is a mainstay treatment for advanced prostate cancer. USP2 stabilises 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 key regulator of proteins involved in prostate cancer progression and therapy resistance, positioning it as a viable therapeutic target.