Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling

Y. C. Liao, J. W. Ruan, I. Lua, M. H. Li, W. L. Chen, J. R.Y. Wang, R. H. Kao, J. H. Chen

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Human pituitary tumour-transforming gene 1 (hPTTG1) is an oncogenic transcription factor that is overexpressed in many tumour types, especially tumours with metastatic abilities. However, how hPTTG1 overexpression drives metastasis is not yet clear. As a transcription factor, hPTTG1 may promote metastasis by activating target genes that are involved in the metastatic process. Here, we showed that Rho guanine nucleotide exchange factor-H1 (GEF-H1) was transcriptionally activated by hPTTG1, thereby promoting breast cancer metastasis. Luciferase reporter analyses and chromatin immunoprecipitation (ChIP) assays showed that hPTTG1 directly bound and activated the GEF-H1 gene promoter. In this study, RNA interference-mediated knockdown of hPTTG1 in highly metastatic breast tumour cells decreased GEF-H1 expression and RhoA activation, thereby reducing cell motility and invasion, and interfering with cytoskeletal remodelling in vitro, and impairing the tumour metastasis in vivo. The restoration of GEF-H1 expression in hPTTG1-knockdown cells rescued the hPTTG1-knockdown effects on cytoskeletal changes in vitro and tumour metastasis in vivo. Conversely, ectopic expression of hPTTG1 in non-metastatic breast tumour cells induced cytoskeletal rearrangements, and allowed these cells to metastasise in a mouse model by orthotopic implantation. In human tumour samples, hPTTG1 expression was also correlated to GEF-H1 expression in aggressive breast carcinoma. Altogether, these findings definitively establish a role for hPTTG1 in activating the GEF-H1/RhoA pathway as a newly identified mechanism in breast cancer metastasis.

Original languageEnglish
Pages (from-to)3086-3097
Number of pages12
JournalOncogene
Volume31
Issue number25
DOIs
Publication statusPublished - Jun 21 2012
Externally publishedYes

Keywords

  • cytoskeleton regulation
  • GEF-H1
  • hPTTG1
  • RhoA
  • tumour metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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