BAP1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization

• Type of Material: Article
• Authors: Karen H. Ventii, Emory University; Narra S. Devi, Emory University; Kenneth L. Friedrich, Emory University; Tatiana Chernova, Emory University; Mourad Tighiouart, Emory University; Erwin Van Meir, Emory University; Keith D. Wilkinson, Emory University
• Language: English
• Date: 2008-09-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 American Association for Cancer Research
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/68/17/6953
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 68
• Issue: 17
• Start Page: 6953
• End Page: 6962
• Grant/Funding Information: Grant support: National Institutes of Health (GM30308 to KDW; CA86335 and CA116804 to EGVM; 5K12GM000680 to KLF).; National Institute of General Medical Sciences : NIGMS
• Keywords: ubiquitin; cancer; BRCA1; BAP1
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

BAP1 (BRCA1-associated protein-1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have demonstrated for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice. We show that BAP1 fulfills another criterion of a genuine tumor suppressor because cancer-associated mutations in BAP1 result in a protein deficient in deubiquitinating activity. We show for the first time that one of the two predicted nuclear targeting motifs is required for nuclear localization of BAP1 and that a truncation mutant found in a lung cancer cell line results in BAP1 that fails to localize to the nucleus. Furthermore, we demonstrate that deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression in nude mice. We show that BAP1 exerts its tumor suppressor functions by affecting the cell cycle; speeding the progression through the G1/S checkpoint and inducing cell death via a process that has characteristics of both apoptosis and necrosis. Surprisingly, BAP1-mediated growth suppression is independent of wild-type BRCA1. Since deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anti-cancer drugs. The identification of the deubiquitinating enzyme BAP1 as a tumor suppressor may lead to further understanding of how the ubiquitin proteasome system contributes to cancer and aid in the identification of new targets for cancer therapy.