2. Academic Validation
  3. OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR

OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR

  • Commun Biol. 2022 Mar 1;5(1):182. doi: 10.1038/s42003-022-03133-1.
Xuhong Fu  # 1,  Junjie Zhao  # 2,  Guopeng Yu  # 3,  Xiaomin Zhang 4,  Jie Sun 2,  Lingmeng Li 1,  Jingyi Yin 1,  Yinan Niu 1,  Shancheng Ren 4,  Yasheng Zhu 5,  Bin Xu 6,  Liyu Huang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2 Department of General Surgery, Zhongshan Hospital, General Surgery Research Institute, Fudan University, Shanghai, 200032, China.
  • 3 Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 4 Department of Urology, Shanghai Changhai Hospital, Shanghai, 200433, China.
  • 5 Department of Urology, Shanghai Changhai Hospital, Shanghai, 200433, China. zys0562@foxmail.com.
  • 6 Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. chxb2004@126.com.
  • 7 Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China. huangly@sjtu.edu.cn.
  • # Contributed equally.
PMID: 35233061 DOI: 10.1038/s42003-022-03133-1
Abstract

Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, Ferroptosis and tumorigenesis; however, their pathological roles in prostate Cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic amplification in PCa, among which ovarian tumor Deubiquitinase 6A (OTUD6A) amplified in the top around 15-20%. Further clinical investigation showed that the OTUD6A protein was highly expressed in prostate tumors, and increased OTUD6A expression correlated with a higher biochemical recurrence risk after prostatectomy. Biologically, wild-type but not a catalytically inactive mutant form of OTUD6A was required for PCa cell progression. In vivo experiments demonstrated that OTUD6A Oligonucleotides markedly suppressed prostate tumorigenesis in PTENPC-/- mice and patient-derived xenograft (PDX) models. Mechanistically, the SWI/SNF ATPase subunit Brg1 and the nuclear receptor AR (Androgen Receptor) were identified as essential substrates for OTUD6A in PCa cells by a mass spectrometry (MS) screening approach. Furthermore, OTUD6A stabilized these two proteins by erasing the K27-linked polyubiquitination of Brg1 and K11-linked polyubiquitination of AR. OTUD6A amplification exhibited strong mutual exclusivity with mutations in the tumor suppressors FBXW7 and SPOP. Collectively, our results indicate the therapeutic potential of targeting OTUD6A as a Deubiquitinase of Brg1 and AR for PCa treatment.

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