Histone Deacetylase Inhibitor Activates the p21/WAF1/Cip1 Gene Promoter through the Sp1 Sites

Sowa, Yoshihiro; Orita, Tetsuro; Hiranabe-Minamikawa, S.; Nakano, Katsunori; Mizuno, Takakazu; Nomura, Hitoshi; Sakai, Toshiyuki

doi:10.1111/j.1749-6632.1999.tb09415.x

Cited by 118 publications

(109 citation statements)

References 8 publications

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“…Critically, the principal mechanism of growth inhibition appeared to be induction of apoptosis rather than cell cycle arrest, supporting further a diminished role for p21 (waf1/cip1) in mediating the antiproliferative e ects. Thus, although we cannot exclude a contribution from transcriptional upregulation of p21 (waf1/cip1) by 1a,25(OH) 2 D 3 and NaB, via speci®c NaB-response elements (Pace et al, 2000;Iowa et al, 1999), we believe the contribution at the dose used in the current study, is minimal.…”

Section: Discussionmentioning

confidence: 83%

Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

et al. 2001

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Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1a,25 Dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) in regulating the growth and di erentiation of the normal prostate gland yet prostate cancer cells appear signi®cantly less sensitive to this action. Vitamin D 3 receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative e ects of 1a,25(OH) 2 D 3 and therefore it is unclear why prostate cancer cell lines are signi®cantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1a,25(OH) 2 D 3 are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 mM and 15 nM respectively), which alone were relatively inactive, synergized with 1a,25(OH) 2 D 3 in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D 3 hexa¯uoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclindependent kinase inhibitor, p21 (waf1/cip1) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1a,25(OH) 2 D 3 during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D 3 analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgendependent and independent prostate cancer. Oncogene (2001) 20, 1860 ± 1872.

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Section: Discussionmentioning

confidence: 83%

Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

et al. 2001

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“…It has been proposed that p21 WAF1/Cip1 could be one of the better candidates for gene-regulating chemotherapy or chemoprevention, because it is mutated less frequently than p53 gene in human common cancers (Hollstein et al, 1991;Chedid et al, 1994;Li et al, 1995) and its induction by HDAC inhibitors is mediated by a p53-independent pathway (Nakano et al, 1997;Sowa et al, 1999;Huang et al, 2000;Han et al, 2001). It is, therefore, important to understand the induction mechanism of p21 WAF1/Cip1 by HDAC inhibitors in chemotherapy or chemoprevention.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence suggests that the induction of p21 WAF1/Cip1 by these stimuli could be regulated by various signal transduction pathways that mediate cell growth, differentiation, and stress response (Hu et al, 1999;Lee et al, 2000;Mitsuuchi et al, 2000). Also, it has been demonstrated that p21 WAF1/Cip1 induction by HDAC inhibitors was mediated via Sp1 sites through Sp1 family transcription factors, Sp1 and/or Sp3 (Nakano et al, 1997;Sowa et al, 1999;Huang et al, 2000;Han et al, 2001). However, the detailed signal transduction pathways involved in p21 WAF1/Cip1 gene regulation by HDAC inhibitors still remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

et al. 2003

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We previously reported that the activation of p21 WAF1/Cip1 transcription by histone deacetylase inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKCe dominant-negative mutant, and antisense oligonucleotide to inhibit PKCe specifically, we found that among PKC isoforms, PKCe was required for the p21 WAF1/ Cip1 expression by apicidin. In addition to PKCe, PI 3-kinase appeared to participate in the activation of p21 WAF1/Cip1 promoter by apicidin, since inactivation of PI 3-kinase either by transient expression of dominantnegative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21 WAF1/Cip1 promoter and p21 WAF1/Cip1 protein expression by apicidin. Furthermore, membrane translocation of PKCe in response to apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKCe in the p21 WAF1/Cip1 promoter activation by apicidin. However, the p21 WAF1/Cip1 expression by apicidin appeared to be independent of the histone hyperacetylation, since apicidin-induced histone hyperacetylation of p21 WAF1/Cip1 promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21 WAF1/Cip1 by apicidin. Taken together, these results suggest that the PI 3-kinase-PKCe signaling pathway plays a pivotal role in the expression of the p21 WAF1/Cip1 by apicidin.

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“…Our previous chromatin immunoprecipitation data showed that Zac1 might be recruited to the p21 promoter through the Sp1 sites (13), similar to HDAC1 for this promoter (34). We wished to determine whether HDAC1 was involved in the regulation of the p21 gene via p53, Zac1, or both combinations.…”

Section: Physical Interaction Between Zac1 and Hdac1mentioning

confidence: 99%

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

Liu

Chan

Lin

et al. 2008

Molecular Cancer Research

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Zac1 is a novel seven -zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21 WAF1/Cip1 promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21 WAF1/Cip1 gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A -induced p21 WAF1/Cip1 protein expression might be mediated through a p53-independent and HDAC deacetylaseindependent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21 WAF1/Cip1 gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.

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Histone Deacetylase Inhibitor Activates the p21/WAF1/Cip1 Gene Promoter through the Sp1 Sites

Cited by 118 publications

References 8 publications

Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathway

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

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