TRIM36 regulates neuroendocrine differentiation of prostate cancer via HK2 ubiquitination and GPx4 deficiency

Abstract

Abstract Neuroendocrine prostate cancer (NEPC) arises from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT), which belongs to the most lethal subtype of castration-resistant prostate cancer (PCa). ADT paradoxically promoted the incidence of NEPC, with a mechanism awaiting to be clarified. Trigred motif 36 (TRIM36), a member of the trim protein family, participates in a variety of cellular processes. Our previous experimental results have confirmed that TRIM36 was highly expressed in PCa and inhibited the invasion and proliferation of PCa. In this study, we found that TRIM36 was associated with the neuroendocrine differentiation (NED) phenotype. TRIM36 was found to inhibit the NEPC of the PCa cell lines LNCaP and PC3. The autophagic degradation of HK2 (hexokinase 2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose-6-phosphate, was found to be involved in the regulation of glycolysis by autophagy. TRIM36 specifically bound to HK2 and inhibited the glycolysis of PCa cells through lysine 48 (lys48)-mediated ubiquitination of HK2. The degradation of HK2 reduced the expression of GPX4, a protein that inhibits ferroptosis, a novel form of nonapoptotic programmed cell death. Ferroptosis enhancement can further inhibit the NED of PCa cells. In conclusion, TRIM36 can ubiquitinate HK2, inhibit glycolysis in PCa cells, inhibit GPX4 activity, promote ferroptosis of PCa cells, and then inhibit their NED. Our study may design new strategies to retard NED and treat NEPC.