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Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT

F L Delarue1, J Adnane, B Joshi

  • 1Drug Discovery Program at H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Oncogene
|August 16, 2006
PubMed

Insights

Novel anticancer agents, farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase I inhibitors (GGTIs), upregulate RhoB expression in various human cancers. This occurs via transcriptional regulation and promoter acetylation, offering a new therapeutic mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • RhoB protein plays a crucial role in suppressing malignant transformation and metastasis.
  • EGFR, ErbB2, Ras, and Akt signaling pathways are implicated in cancer progression.

Purpose of the Study:

  • To investigate the effect of farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase I inhibitors (GGTIs) on RhoB expression in human cancer cells.
  • To elucidate the regulatory mechanism of RhoB induction by FTIs and GGTIs.

Main Methods:

  • Treatment of various human cancer cell lines (pancreatic, breast, lung, colon, bladder, brain) with FTIs (e.g., FTI-277) and GGTIs (e.g., GGTI-298).
  • Analysis of RhoB expression levels using Western blotting and reverse transcription-PCR.
  • Assessment of transcriptional regulation using actinomycin D.
  • Chromatin immunoprecipitation assays to study histone modifications (acetylation) and protein interactions (HDAC1, HAT) at the RhoB promoter.

Main Results:

  • FTIs and GGTIs significantly upregulate RhoB expression across a wide spectrum of human cancer cells.
  • RhoB induction is mediated at the transcriptional level, as evidenced by increased RhoB transcription and blockage by actinomycin D.
  • Anticancer agent treatment leads to dissociation of HDAC1, association of HAT, and histone acetylation of the RhoB promoter.

Conclusions:

  • FTIs and GGTIs represent novel therapeutic agents that can upregulate RhoB expression in cancer cells.
  • RhoB promoter acetylation is identified as a novel mechanism regulating RhoB expression in response to FTIs and GGTIs.
  • Targeting RhoB expression through promoter acetylation may offer a new strategy for cancer therapy.

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