title: Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma.
abstract: BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that is involved in the regulation of cell growth. Recently, many somatic and germline mutations of BAP1 have been reported in a broad spectrum of tumors. In this study, we identified a novel somatic non-synonymous BAP1 mutation, a phenylalanine-to-isoleucine substitution at codon 170 (F170I), in 1 of 49 patients with esophageal squamous cell carcinoma (ESCC). Multiplex ligation-dependent probe amplification (MLPA) of BAP1 gene in this ESCC tumor disclosed monoallelic deletion (LOH), suggesting BAP1 alterations on both alleles in this tumor. The deubiquitinase activity and the auto-deubiquitinase activity of F170I-mutant BAP1 were markedly suppressed compared with wild-type BAP1. In addition, wild-type BAP1 mostly localizes to the nucleus, whereas the F170I mutant preferentially localized in the cytoplasm. Microarray analysis revealed that expression of the F170I mutant drastically altered gene expression profiles compared with expressed wild-type BAP1. Gene-ontology analyses indicated that the F170I mutation altered the expression of genes involved in oncogenic pathways. We found that one candidate, TCEAL7, previously reported as a putative tumor suppressor gene, was significantly induced by wild-type BAP1 as compared to F170I mutant BAP1. Furthermore, we found that the level of BAP1 expression in the nucleus was reduced in 44% of ESCC examined by immunohistochemistry (IHC). Because the nuclear localization of BAP1 is important for its tumor suppressor function, BAP1 may be functionally inactivated in a substantial portion of ESCC. Taken together, BAP1 is likely to function as a tumor suppressor in at least a part of ESCC.
authors.affiliation: Tohoku Community Cancer Services Program, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mori
authors.affiliation: Tohoku Community Cancer Services Program, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Sumii
authors.affiliation: Department of Pathology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Fujishima
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Ueno
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
authors.affiliation: Department of Cancer Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Chiba
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D003593:Cytoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D009687:Nuclear Proteins; C503109:TCEAL7 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1; deubiquitinase; esophageal squamous cell carcinoma; gene expression profiling; somatic mutation