The cAMP responsive element binding protein 1 transactivates epithelial membrane protein 2, a potential tumor suppressor in the urinary bladder urothelial carcinoma

Chien Feng Li, Wen Jeng Wu, Wen Ren Wu, Yu Jing Liao, Lih Ren Chen, Chun Nung Huang, Ching Chia Li, Wei Ming Li, Hsuan Ying Huang, Yi Ling Chen, Shih Shin Liang, Nan Haw Chow, Yow Ling Shiue

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

In this study, we report that EMP2 plays a tumor suppressor role by inducing G2/M cell cycle arrest, suppressing cell viability, proliferation, colony formation/ anchorage-independent cell growth via regulation of G2/M checkpoints in distinct urinary bladder urothelial carcinoma (UBUC)-derived cell lines. Genistein treatment or exogenous expression of the cAMP responsive element binding protein 1 (CREB1) gene in different UBUC-derived cell lines induced EMP2 transcription and subsequent translation. Mutagenesis on either or both cAMP-responsive element(s) dramatically decreased the EMP2 promoter activity with, without genistein treatment or exogenous CREB1 expression, respectively. Significantly correlation between the EMP2 immunointensity and primary tumor, nodal status, histological grade, vascular invasion and mitotic activity was identified. Multivariate analysis further demonstrated that low EMP2 immunoexpression is an independent prognostic factor for poor disease-specific survival. Genistein treatments, knockdown of EMP2 gene and double knockdown of CREB1 and EMP2 genes significantly inhibited tumor growth and notably downregulated CREB1 and EMP2 protein levels in the mice xenograft models. Therefore, genistein induced CREB1 transcription, translation and upregulated pCREB1(S133) protein level. Afterward, pCREB1(S133) transactivated the tumor suppressor gene, EMP2, in vitro and in vivo. Our study identified a novel transcriptional target, which plays a tumor suppressor role, of CREB1.

Original languageEnglish
Pages (from-to)9220-9239
Number of pages20
JournalOncotarget
Volume6
Issue number11
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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