Steroidogenic enzymes are crucial in prostate cancer (PCa) progression. 17β-Hydroxysteroid dehydrogenase type 4 (HSD17B4), encoded by HSD17B4, lacks catalytic capacity in androgen metabolism. Now the detailed role and molecular mechanism of PCa development are largely unknown. Here we showed that the expression of HSD17B4 was increased in PCa tissues compared to paired paratumor tissues. HSD17B4 knockdown in PCa cells significantly suppressed its proliferation, migration and invasion, while overexpressing HSD17B4 had opposite effects. Mechanistically, we found that the protein level of HSD17B4 was regulated by its acetylation at lysine 669(K669). Dihydroxytestosterone (DHT) treatment increased HSD17B4 acetylation and then promoted its degradation via chaperone-mediated autophagy (CMA). SIRT3 directly interacted with HSD17B4 to inhibit its acetylation and enhance its stability. In addition, we identified CREBBP as a regulator of the K669 acetylation and degradation of HSD17B4, affecting PC cell proliferation, migration and invasion. Notably, in PCa tissues and paired paratumor tissues, the level of HSD17B4 was negatively correlated with its K669 acetylation. Taken together, this study identified a novel role of HSD17B4 in PCa progression and suggested that HSD17B4 and its upstream regulators may be potential therapeutic targets for PCa intervention.
Aging. 2020 Jul 17 [Epub ahead of print]
Huichao Huang, Ruijie Liu, Yahui Huang, Yilu Feng, Ying Fu, Lin Chen, Zhuchu Chen, Yi Cai, Ye Zhang, Yongheng Chen
Department of Oncology, NHC Key Laboratory of Cancer Proteomics, XiangYa Hospital, Central South University, Changsha 410008, China., Department of Pathology, XuChang Central Hospital, XuChang 461670, China., Molecular and Computational Biology Program, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, CA 90089, USA., Department of Urology, XiangYa Hospital, Central South University, Changsha 410008, China.