OTUD4 Inhibits Prostate Cancer by Deubiquitinating MYH9

Prostate cancer is the second most common fatal cancer in men. Identifying new biological therapeutic targets is crucial to effectively improve the prognosis of prostate cancer patients. Ovarian tumor family deubiquitinase 4 (OTUD4) is a member of the ovarian tumor-associated protease domain (OTUDs) family. Although previous studies have shown that the expression and function of OTUD4 vary across different tumors, its role in prostate cancer remains unknown. The aim of this study is to explore new therapeutic targets and diagnostic markers for prostate cancer and investigate their mechanisms of action.

Cell culture, Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Transwell assay, 5-Ethynyl-2^′-deoxyuridine (EdU) assay, immunofluorescence, Western blot, Quantitative real-time PCR (qRT-PCR), protein mass spectrometry, nude mouse xenograft models, immunohistochemistry (IHC), and hematoxylin and eosin (H&E) staining were utilized.

We found that OTUD4 expression was reduced in prostate cancer and negatively correlated with poor prognosis in both in vivo and in vitro experiments. Subsequent mechanistic studies revealed that OTUD4 directly inhibits the degradation of myosin-9 (MYH9) protein via deubiquitination. Although MYH9 has been previously reported to act as a tumor suppressor in prostate cancer, no experimental evidence had demonstrated that MYH9 inhibits prostate cancer growth. Our results indicate that MYH9 overexpression effectively suppresses prostate cancer through interactions with cell adhesion molecules.

Collectively, these results suggest that OTUD4 functions as a tumor suppressor in prostate cancer. Specifically, OTUD4 inhibits MYH9 degradation via deubiquitination, thereby enabling MYH9-mediated suppression of prostate cancer.