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 journalArticle

37 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

Fingerprint

Guanine Nucleotide Exchange Factors
Pituitary Neoplasms
Oncogenes
Breast Neoplasms
Neoplasm Metastasis
Gene Knockdown Techniques
Neoplasms
Transcription Factors
Rho Guanine Nucleotide Exchange Factors
Chromatin Immunoprecipitation
RNA Interference
Luciferases
Genes
Cell Movement

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Liao, Y. C., Ruan, J. W., Lua, I., Li, M. H., Chen, W. L., Wang, J. R. Y., ... Chen, J. H. (2012). Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling. Oncogene, 31(25), 3086-3097. https://doi.org/10.1038/onc.2011.476

Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling. / Liao, Y. C.; Ruan, J. W.; Lua, I.; Li, M. H.; Chen, W. L.; Wang, J. R.Y.; Kao, R. H.; Chen, J. H.

In: Oncogene, Vol. 31, No. 25, 21.06.2012, p. 3086-3097.

Research output: Contribution to journalArticle

Liao, YC, Ruan, JW, Lua, I, Li, MH, Chen, WL, Wang, JRY, Kao, RH & Chen, JH 2012, 'Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling', Oncogene, vol. 31, no. 25, pp. 3086-3097. https://doi.org/10.1038/onc.2011.476
Liao, Y. C. ; Ruan, J. W. ; Lua, I. ; Li, M. H. ; Chen, W. L. ; Wang, J. R.Y. ; Kao, R. H. ; Chen, J. H. / Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling. In: Oncogene. 2012 ; Vol. 31, No. 25. pp. 3086-3097.
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