title: BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.
abstract: The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Here we show that, in breast cancer cells, KLF5 is stabilized by the deubiquitinase (DUB) BAP1. With a genome-wide siRNA library screen of DUBs, we identify BAP1 as a bona fide KLF5 DUB. BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5. Collectively, our findings not only identify BAP1 as the DUB for KLF5, but also reveal a critical mechanism that regulates KLF5 expression in breast cancer. Our findings indicate that BAP1 could be a potential therapeutic target for breast and other cancers.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.|Graduate School of the Chinese Academy of Sciences, Beijing 100039, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Qin
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Breast Surgery, Breast Cancer Clinical Research Center, Cancer Hospital, Kunming Medical University, Kunming, Yunnan 650031, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.|Graduate School of the Chinese Academy of Sciences, Beijing 100039, China.|Department of Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.|Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
authors.forename: Guangzhe
authors.initials: G
authors.lastname: Ge
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.|Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shao
authors.affiliation: Kunming Medical University, Kunming, Yunnan 650031, China.
authors.forename: Dingyun
authors.initials: D
authors.lastname: You
authors.affiliation: Kunming Medical University, Kunming, Yunnan 650031, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.
authors.forename: Houjun
authors.initials: H
authors.lastname: Xia
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.
authors.forename: Ceshi
authors.initials: C
authors.lastname: Chen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011485:Protein Binding; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C400134:BAP1 protein, human; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase