Histone Deacetylase Inhibitor Activates the WAF1/Cip1 Gene Promoter through the Sp1 Sites

Sowa, Yoshihiro; Orita, Tetsuro; Minamikawa, Sachie; Nakano, Katsunori; Mizuno, Takakazu; Nomura, Hitoshi; Sakai, Toshiyuki

doi:10.1006/bbrc.1997.7786

Cited by 284 publications

(241 citation statements)

References 26 publications

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“…Several important biological modifiers have been shown to activate p21 transcription through different Spl binding sites (Cartel and Tyner, 1999). For example, phorbol ester and okadaic acid induce p21 expression through Spl-1 and Spl-2 sites (Biggs et al, 1996), whereas the Spl-3 site in the promoter of p21 has been shown to be required for p21 induction by transforming growth factor-b, histone deacetylase inhibitors such as TSA and butyrate, lovastatin, nerve growth factor (NGF) as well as calcium (Datto et al, 1995;Nakano et al, 1997;Prowse et al, 1997;Sowa et al, 1997;Lee et al, 1998;Billon et al, 1999). In this report, we demonstrated that Spl-3 and Spl-4 in the promoter of human p21 gene are required for vinorelbinemediated transcriptional restoration of p21 in the p21-deficient Al cells, which may provide a new mechanism in drug-mediated p21 regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The fulllength promoter is a 2.4-kb genomic fragment subcloned into the HindIII site of the luciferase reporter vector, pGL2-basic (Promega, Madison, WI, USA) (Datto et al, 1995). The pWPdel-BstX I(À133 to þ 1 relative to the start site) contains all six Sp-1 sites without the p53 binding site Sowa et al, 1997). The pWPlOl, by deleting Spl-1 and Spl-2 from pWPdel -BstXI, consists of a minimal promoter region of 101 relative to the transcriptional start site containing four Spl binding sites, termed Spl-3, Spl-4 Spl-5, and Spl-6.…”

Section: P21 Constructsmentioning

confidence: 99%

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Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

et al. 2003

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To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21 WAFl/CIP1 (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Section: P21 Constructsmentioning

confidence: 99%

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

et al. 2003

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“…To examine the effect of DHCB on the transcriptional activity of p21, we transiently transfected cells with 1 µg of plasmid containing a 2.4 kb genomic fragment of the p21 promoter cloned upstream of the LUC reporter gene [29], using the calcium phosphate transfection kit from Promega Biosciences (St. Louis, MO, USA). Twenty four hours after transfection, cells were treated with DHCB at increasing concentrations for 12 hours.…”

Section: Transfection and Reporter Assaysmentioning

confidence: 99%

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Escandell

Kaler

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et al. 2008

Biochemical Pharmacology

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Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We compared the activity of 23, 24-dihydrocucurbitacin B (DHCB) and cucurbitacin R (CCR), two cucurbitacins that we recently isolated, with cucurbitacin I (CCI), a cucurbitacin with established antitumorigenic activity. We showed that cucurbitacins induced dramatic changes in the cytoskeleton (collapse of actin and bundling of tubulin microfilaments), inhibited proliferation and finally induced apoptosis of both HCT116 and Hke3 cells. However, the presence of oncogenic k-Ras significantly decreased the sensitivity of cells to the three cucurbitacins tested, CCR, DHCB and CCI. We confirmed that mutational activation of kRas protects cells from cucurbitacin-induced apoptosis using nontransfromed intestinal epithelial cells with inducible expression of k-RasV12. Cucurbitacins induced the expression of p53 and p21 predominantly in HCT116 cells that harbor mutant Ras. Using HCT116 cells with targeted deletion of p53 or p21 we confirmed that p53 and p21 protect cells from apoptosis induced by cucurbitacins. These results demonstrated that sensitivity of human colon cancer cell lines to cucurbitacins depends on the kRas and p53/p21 status, and established that cucurbitacins can exert antitumorigenic activity in the absence of activated STAT3.

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“…One very prominent effect observed for a large panel of HDAC inhibitors is induction of p21 (Archer et al, 1998;Kim et al, 2001;Sowa et al, 1997;Wilson et al, 2006). Hence, we determined p21 expression levels upon HDAC inhibitor treatment alone and in combination with PKC412.…”

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confidence: 99%

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS) which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease.Recently, we were able to demonstrate that the small molecule inhibitor PKC412 (midostaurin) exhibits strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR.Here, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase (HDAC) inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo.We provide evidence that the antitumor effect upon combination treatment is achieved by VPAinduced reactivation of p21 which is downregulated in aRMS cells via destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

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Histone Deacetylase Inhibitor Activates the WAF1/Cip1 Gene Promoter through the Sp1 Sites

Cited by 284 publications

References 26 publications

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

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