Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

F. L. Delarue, J. Adnane, B. Joshi, M. A. Blaskovich, D. A. Wang, J. Hawker, F. Bizouarn, J. Ohkanda, K. Zhu, A. D. Hamilton, S. Chellappan, S. M. Sebti

Research output: Contribution to journalArticlepeer-review

Abstract

Recently, we have shown that RhoB suppresses EGFR-, ErbB2-, Ras- and Akt-mediated malignant transformation and metastasis. In this paper, we demonstrate that the novel antitumor agents farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase I inhibitors (GGTIs) upregulate RhoB expression in a wide spectrum of human cancer cells including those from pancreatic, breast, lung, colon, bladder and brain cancers. RhoB induction by FTI-277 and GGTI-298 occurs at the transcriptional level and is blocked by actinomycin D. Reverse transcription-PCR experiments documented that the increase in RhoB protein levels is due to an increase in RhoB transcription. Furthermore, treatment with FTIs and GGTIs of cancer cells results in HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Thus, promoter acetylation is a novel mechanism by which RhoB expression levels are regulated following treatment with the anticancer agents FTIs and GGTIs.

Original languageEnglish (US)
Pages (from-to)633-640
Number of pages8
JournalOncogene
Volume26
Issue number5
DOIs
StatePublished - Feb 1 2007

Keywords

  • Farnesyltransferase inhibitors
  • Geranylgeranyltransferase inhibitors
  • HAT association
  • HDAC1 dissociation
  • Histone acetylation
  • RhoB

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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