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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Adnane J, Bizouarn FA, Chen Z, Ohkanda J, Hamilton AD, Munoz-Antonia T et al. (2000). Inhibition of farnesyltransferase increases TGFbeta type II receptor expression and enhances the responsiveness of human cancer cells to TGFbeta. Oncogene 19: 5525–5533.
Adnane J, Muro-Cacho C, Mathews L, Sebti SM, Munoz-Antonia T . (2002). Suppression of RhoB expression in invasive carcinoma from head and neck cancer patients. Clin Cancer Res 8: 2225–2232.
Baron R, Fourcade E, Lajoie-Mazenc I, Allal C, Couderc B, Barbaras R et al (2000). RhoB prenylation is driven by the three carboxyl-terminal amino acids of the protein: evidenced in vivo by an anti-farnesyl cysteine antibody. Proc Natl Acad Sci USA 97: 11626–11631.
Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE et al. (1998). A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. Mol Cell Biol 18: 85–92.
Benjamin D, Jost JP . (2001). Reversal of methylation-mediated repression with short-chain fatty acids: evidence for an additional mechanism to histone deacetylation. Nucleic Acids Res 29: 3603–3610.
Chaya D, Hayamizu T, Bustin M, Zaret KS . (2001). Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin. J Biol Chem 276: 44385–44389.
Chen Z, Sun J, Pradines A, Favre G, Adnane J, Sebti SM . (2000). Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J Biol Chem 275: 17974–17978.
Cox AD, Der CJ . (1997). Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1333: F51–71.
Dasgupta P, Betts V, Rastogi S, Joshi B, Morris M, Brennan B et al. (2004). Direct binding of apoptosis signal-regulating kinase 1 to retinoblastoma protein: novel links between apoptotic signaling and cell cycle machinery. J Biol Chem 279: 38762–38769.
Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K . (2003). The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 100: 8758–8763.
Du W, Prendergast GC . (1999). Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res 59: 5492–5496.
Fritz G, Gnad R, Kaina B . (1999). Cell and tissue-type specific expression of Ras-related GTPase RhoB. Anticancer Res 19: 1681–1688.
Fritz G, Kaina B . (2000). Ras-related GTPase RhoB forces alkylation-induced apoptotic cell death. Biochem Biophys Res Commun 268: 784–789.
Fritz G, Kaina B, Aktories K . (1995). The ras-related small GTP-binding protein RhoB is immediate-early inducible by DNA damaging treatments. J Biol Chem 270: 25172–25177.
Fusaro G, Dasgupta P, Rastogi S, Joshi B, Chellappan S . (2003). Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling. J Biol Chem 278: 47853–47861.
Gibbs JB, Oliff A . (1997). The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol 37: 143–166.
Gui CY, Dean A . (2001). Acetylation of a specific promoter nucleosome accompanies activation of the epsilon-globin gene by beta-globin locus control region HS2. Mol Cell Biol 21: 1155–1163.
Holstein SA, Wohlford-Lenane CL, Hohl RJ . (2002a). Consequences of mevalonate depletion. Differential transcriptional, translational, and post-translational up-regulation of Ras, Rap1a, RhoA, and RhoB. J Biol Chem 277: 10678–10682.
Holstein SA, Wohlford-Lenane CL, Hohl RJ . (2002b). Isoprenoids influence expression of Ras and Ras-related proteins. Biochemistry 41: 13698–13704.
Hunt JT, Ding CZ, Batorsky R, Bednarz M, Bhide R, Cho Y et al. (2000). Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)- 3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS- 214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem 43: 3587–3595.
Jiang K, Delarue FL, Sebti SM . (2004a). EGFR, ErbB2 and Ras but not Src suppress RhoB expression while ectopic expression of RhoB antagonizes oncogene-mediated transformation. Oncogene 23: 1136–1145.
Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S . (2004b). Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 24: 5565–5576.
Kohl NE, Wilson FR, Mosser SD, Giuliani E, deSolms SJ, Conner MW et al. (1994). Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA 91: 9141–9145.
Lebowitz PF, Casey PJ, Prendergast GC, Thissen JA . (1997). Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J Biol Chem 272: 15591–15594.
Lebowitz PF, Prendergast GC . (1998). Non-Ras targets of farnesyltransferase inhibitors: focus on Rho. Oncogene 17: 1439–1445.
Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J et al. (1995). Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras–Raf complexes. J Biol Chem 270: 26802–26806.
Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM . (1997). Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15: 1283–1288.
Liu A, Du W, Liu JP, Jessell TM, Prendergast GC . (2000). RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol Cell Biol 20: 6105–6113.
Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P et al. (1998). Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 58: 4947–4956.
Mazieres J, Antonia T, Daste G, Muro-Cacho C, Berchery D, Tillement V et al. (2004). Loss of RhoB expression in human lung cancer progression. Clin Cancer Res 10: 2742–2750.
Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM . (1995). Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 55: 5310–5314.
Pan J, She M, Xu ZX, Sun L, Yeung SC . (2005). Farnesyltransferase inhibitors induce DNA damage via reactive oxygen species in human cancer cells. Cancer Res 65: 3671–3681.
Prendergast GC . (2001). Actin' up: rhoB in cancer and apoptosis. Nat Rev Cancer 1: 162–168.
Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM . (1997). Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 272: 14093–14097.
Sebti SM, Der CJ . (2003). Opinion: searching for the elusive targets of farnesyltransferase inhibitors. Nat Rev Cancer 3: 945–951.
Sebti SM, Hamilton AD . (2000). Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues. Expert Opin Invest Drugs 9: 2767–2782.
Sun J, Qian Y, Hamilton AD, Sebti SM . (1998). Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 16: 1467–1473.
Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM . (1997). The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem 272: 27224–27229.
Wang S, Yan-Neale Y, Fischer D, Zeremski M, Cai R, Zhu J et al. (2003). Histone deacetylase 1 represses the small GTPase RhoB expression in human nonsmall lung carcinoma cell line. Oncogene 22: 6204–6213.
Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ . (2001). Use of chromatin immunoprecipitation to clone novel E2F target promoters. Mol Cell Biol 21: 6820–6832.
Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ et al. (1997). K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272: 14459–14464.
Zhang FL, Casey PJ . (1996). Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65: 241–269.
Zohn IM, Campbell SL, Khosravi-Far R, Rossman KL, Der CJ . (1998). Rho family proteins and Ras transformation: the RHOad less traveled gets congested. Oncogene 17: 1415–1438.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Delarue, F., Adnane, J., Joshi, B. et al. Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Oncogene 26, 633–640 (2007). https://doi.org/10.1038/sj.onc.1209819
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209819
Keywords
This article is cited by
-
Rho GTPases in cancer radiotherapy and metastasis
Cancer and Metastasis Reviews (2020)
-
Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases
Cellular and Molecular Life Sciences (2018)
-
Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells
Scientific Reports (2017)
-
A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS-mediated c-Abl/p38 MAPK signaling
Cancer Chemotherapy and Pharmacology (2013)
-
Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors
Nature Protocols (2011)