Trigred motif 36 regulates neuroendocrine differentiation of prostate cancer via HK2 ubiquitination and GPx4 deficiency

• Published in: Cancer science 2023-06, Vol.114 (6), p.2445-2459
• Main Authors: Zhao, Xusong, Zhou, Tianren, Wang, Yuhao, Bao, Meiling, Ni, Chenbo, Ding, Lei, Sun, Shengjie, Dong, Huiyu, Li, Jie, Liang, Chao
• Format: Article
• Language: English
• Subjects: Adhesives; Androgens; Anti-oncogenes; Antibodies; Biotechnology; Cancer therapies; Castration; Cell differentiation; Ferroptosis; Glucose; Glutathione peroxidase; Glycolysis; Hexokinase; HK2; Kinases; Mass spectrometry; Molecular modelling; NED; Original; ORIGINAL ARTICLES; Patients; PCa; Peptides; Prostate cancer; Proteins; Proteomics; Scientific imaging; Software; TRIM36; Tumors; Ubiquitination
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15763

Neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration‐resistant prostate cancer (PCa), may evolve from the neuroendocrine differentiation (NED) of PCa cells. However, the molecular mechanism that triggers NED is unknown. Trigred motif 36 (TRIM36), a member of the TRIM protein family, exhibits oncogenic or anti‐oncogenic roles in various cancers. We have previously reported that TRIM36 is highly expressed to inhibit the invasion and proliferation of PCa. In the present study, we first found that TRIM36 was lowly expressed in NEPC and its overexpression suppressed the NED of PCa. Next, based on proteomic analysis, we found that TRIM36 inhibited the glycolysis pathway through suppressing hexokinase 2 (HK2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose‐6‐phosphate. TRIM36 specifically bound to HK2 through lysine 48 (lys48)‐mediated ubiquitination of HK2. Moreover, TRIM36‐mediated ubiquitination degradation of HK2 downregulated the level of glutathione peroxidase 4 (GPx4), a process that contributed to ferroptosis. In conclusion, TRIM36 can inhibit glycolysis via lys48‐mediated HK2 ubiquitination to reduce GPX4 expression and activate ferroptosis, thereby inhibiting the NED in PCa. Targeting TRIM36 might be a promising approach to retard NED and treat NEPC. TRIM36 can promote the occurrence of ferroptosis and finally inhibit the NED of PCa (prostate cancer) cells by inhibiting the ferroptosis‐related gene glutathione peroxidase 4 through hexokinase 2 in the ubiquitin glycolysis pathway. This mechanism has great potential to design new strategies to retard NEPC and may help prostate cancer researchers to find potential therapeutic targets for treating NEPC.