BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN.

Abstract

BRCA1-associated protein 1 (BAP1) or its mutants have been known to play critical regulatory roles in tumor biology, yet their role in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we detected the mutations of all the exons of BAP1 in 105 HCC patients using Sanger sequencing, and found eight somatic mutations in 6 (5.71%) patients. We also found that the mRNA and protein levels of BAP1 were markedly downregulated in HCC versus the adjacent non-tumor tissues. Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo. Mechanistically, BAP1 complexed with PTEN and stabilized PTEN via deubiquitination and, furthermore, negatively regulated HCC cell EMT by deactivating the AKT/GSK-3β/Snail pathway. However, those tumor-inhibitory effects of BAP1 were abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated to aggressive tumor phenotypes, which also independently associated with poorer recurrence-free survival and overall survival after curative hepatectomy. Conclusively, our results indicate that BAP1, significantly downregulated, somatically mutated and negatively regulating EMT in HCC, serves as a tumor suppressor of HCC by deubiquitinating and stabilizing PTEN.

• Authors: Xuxiao Chen, Ao Huang, Yupeng Wang, Feiyu Chen, Bo Hu, Xin Zhang, Yunfan Sun, Jian Wang, Jianwen Cheng, Pengxiang Wang, Yuan Ji, Shuangjian Qiu, Jia Fan, Jian Zhou, Xinrong Yang
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 11 Issue 5 Pg. 2044-2061 ( 2021) ISSN: 2156-6976 [Print] United States
• PMID: 34094668 (Publication Type: Journal Article)
• Copyright: AJCR Copyright © 2021.