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

Fl, Delarue; Adnane, Jalila; Joshi, Bharat; Ma, Blaskovich; Da, Wang; Hawker, James; Bizouarn, Francisco; Ohkanda, Junko; Zhu, Kuichun; Ad, Hamilton; Chellappan, Srikumar; Sm, Sebti

doi:10.1038/sj.onc.1209819

Cited by 57 publications

(53 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Kip1 and decreasing survivin protein levels, but not with inhibiting Akt activation levels and inducing RhoA and RhoB levels, both of which we have shown previously to be induced by GGTIs (11). These results suggest that, at least in the MiaPaCa2 pancreatic carcinoma cells, the ability of RalB-F to abrogate the GGTI antiproliferative and proapoptotic mechanism of action is associated with abrogation of p27…”

Section: Discussionsupporting

confidence: 51%

Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth

Falsetti

Wang

Peng

et al. 2007

Molecular and Cellular Biology

View full text Add to dashboard Cite

Geranylgeranyltransferase I inhibitors (GGTIs) are presently undergoing advanced preclinical studies and have been shown to disrupt oncogenic and tumor survival pathways, to inhibit anchorage-dependent and -independent growth, and to induce apoptosis. However, the geranylgeranylated proteins that are targeted by GGTIs to induce these effects are not known. Here we provide evidence that the Ras-like small GTPases RalA and RalB are exclusively geranylgeranylated and that inhibition of their geranylgeranylation mediates, at least in part, the effects of GGTIs on anchorage-dependent and -independent growth and tumor apoptosis. To this end, we have created the corresponding carboxyl-terminal mutants that are exclusively farnesylated and verified that they retain the subcellular localization and signaling activities of the wild-type geranylgeranylated proteins and that Ral GTPases do not undergo alternative prenylation in response to GGTI treatment. By expressing farnesylated, GGTI-resistant RalA and RalB in Cos7 cells and human pancreatic MiaPaCa2 cancer cells followed by GGTI-2417 treatment, we demonstrated that farnesylated RalB, but not RalA, confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of GGTI-2417. Conversely, farnesylated RalA but not RalB expression renders MiaPaCa2 cells less sensitive to inhibition of anchorageindependent growth. Furthermore, farnesylated RalB, but not RalA, inhibits the ability of GGTI-2417 to suppress survivin and induce p27Kip1 protein levels. We conclude that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition.

show abstract

Section: Discussionsupporting

confidence: 51%

Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth

Falsetti

Wang

Peng

et al. 2007

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Results were falsely colored black for easier visualization (D). acetylation on the RhoB promoter (41). The incapability of HDACs to bind DNA directly means that HDACs are recruited indirectly to the promoter through associating with the Sp1 transcription factor.…”

Section: Discussionmentioning

confidence: 99%

Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2

et al. 2008

View full text Add to dashboard Cite

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers. In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21 WAF/CIP in human cancer cells. Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a K i value of 31.6 Mmol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays. DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter. In vitro cell proliferation and in vivo tumor growth were both inhibited by statins. These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression. Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention. [Cancer Res 2008;68(7):2375-83]

show abstract

“…Genes involved in cell signalling, such as SQSTM1, which regulates activation of the nuclear factor-kB (NF-kB) signalling pathway, receptor internalisation, and protein turnover, and RRAD, a member of the Ras/GTPase superfamily, are also overexpressed (Moyers et al, 1997;Seibenhener et al, 2007). Genes known to be expressed in CRC were also significantly upregulated, such as HOX2D and RHOB, which mediate apoptosis in neoplastic cells, and are targets for novel antitumour agents, such as farnesyltransferase inhibitors (Vider et al, 1997;Delarue et al, 2007).…”

Section: Functional Annotationmentioning

confidence: 99%

Analysis of differential gene expression in colorectal cancer and stroma using fluorescence-activated cell sorting purification

et al. 2009

View full text Add to dashboard Cite

Tumour stroma gene expression in biopsy specimens may obscure the expression of tumour parenchyma, hampering the predictive power of microarrays. We aimed to assess the utility of fluorescence-activated cell sorting (FACS) for generating cell populations for gene expression analysis and to compare the gene expression of FACS-purified tumour parenchyma to that of whole tumour biopsies. Single cell suspensions were generated from colorectal tumour biopsies and tumour parenchyma was separated using FACS. Fluorescence-activated cell sorting allowed reliable estimation and purification of cell populations, generating parenchymal purity above 90%. RNA from FACS-purified and corresponding whole tumour biopsies was hybridised to Affymetrix oligonucleotide microarrays. Whole tumour and parenchymal samples demonstrated differential gene expression, with 289 genes significantly overexpressed in the whole tumour, many of which were consistent with stromal gene expression (e.g., COL6A3, COL1A2, POSTN, TIMP2 ). Genes characteristic of colorectal carcinoma were overexpressed in the FACS-purified cells (e.g., HOX2D and RHOB ). We found FACS to be a robust method for generating samples for gene expression analysis, allowing simultaneous assessment of parenchymal and stromal compartments. Gross stromal contamination may affect the interpretation of cancer gene expression microarray experiments, with implications for hypotheses generation and the stability of expression signatures used for predicting clinical outcomes.

show abstract

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

Cited by 57 publications

References 39 publications

Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth

Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth

Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2

Analysis of differential gene expression in colorectal cancer and stroma using fluorescence-activated cell sorting purification

Contact Info

Product

Resources

About