Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma

Takahiro Mori, Makiko Sumii, Fumiyoshi Fujishima, Kazuko Ueno, Mitsuru Emi, Masao Nagasaki, Chikashi Ishioka, Natsuko Chiba

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1118-1129
Number of pages12
JournalCancer science
Volume106
Issue number9
DOIs
Publication statusPublished - 2015 Sep 1

Keywords

  • BAP1
  • Deubiquitinase
  • Esophageal squamous cell carcinoma
  • Gene expression profiling
  • Somatic mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma'. Together they form a unique fingerprint.

Cite this