Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

Muscolini, Michela; Cianfrocca, Roberta; Sajeva, Angela; Mozzetti, Simona; Ferrandina, Gabriella; Costanzo, Antonio; Tuosto, Loretta

doi:10.1158/1535-7163.mct-08-0299

Cited by 49 publications

(46 citation statements)

References 47 publications

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“…Interestingly, HDAC inhibitors also induce p21 expression in a p53-independent manner (51). In addition, a recent study showed that despite of induction of p53 upon TSA treatment, up-regulation of p73 contributes to TSA-induced Bax and apoptosis in A2780 ovarian cancer cells (52). Here, we found that like in MCF7 and MCF10A cells containing wide-type p53, DEC1 overexpression or TSA treatment increases ⌬Np63 expression in HaCaT cells containing a mutant p53 (Fig.…”

Section: Discussionsupporting

confidence: 58%

ΔNp63, a Target of DEC1 and Histone Deacetylase 2, Modulates the Efficacy of Histone Deacetylase Inhibitors in Growth Suppression and Keratinocyte Differentiation

Qian

Jung

Chen

2011

Journal of Biological Chemistry

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The p63 gene, a member of the p53 family, is expressed as TA and ⌬N isoforms. ⌬Np63 is the predominant isoform expressed in cells of epithelial origin and frequently overexpressed in cancers. However, what regulates p63 expression is uncertain. Here, we showed that ⌬Np63 is regulated by the transcription factor DEC1, a p53 family target. We also showed that the ability of DEC1 to regulate ⌬Np63 is enhanced by histone deacetylase (HDAC) inhibitors or knockdown of histone deacetylase 2 (HDAC2). Consistent with this, we found that DEC1 and HDAC2 physically interact and knockdown of HDAC2 leads to increased binding of DEC1 to the ⌬Np63 promoter. Interestingly, we found that growth suppression induced by HDAC inhibitors is attenuated by ectopic expression of DEC1 in a ⌬Np63-dependent manner. In addition, we showed that ectopic expression of DEC1 inhibits, whereas knockdown of DEC1 promotes, keratinocyte differentiation via modulating ⌬Np63 expression. Finally, we showed that DEC1 cooperates with HDAC inhibitors to further decrease keratinocyte differentiation. Together, we conclude that ⌬Np63 is a novel target of DEC1 and HDAC2 and modulates the efficacy of HDAC inhibitors in growth suppression and keratinocyte differentiation.p63 shares a similarity with p53 and p73 in sequence-specific DNA binding, activation, and tetramerization domains (1). Like p53, p63 is a transcription factor and capable of inducing a diverse array of target genes responsible for p63 function in inducing cell cycle arrest, differentiation, and apoptosis, and in maintaining the proliferative potential of epithelial stem cells (2-7). Due to the presence of the upstream P1 promoter and the P2 promoter in intron 3, the p63 gene is expressed as TA and ⌬N isoforms (1). TAp63 contains the N-terminal transactivation domain (TA) conserved among the p53 family (1). ⌬Np63 contains 13 unique residues, which together with the prolinerich domain constitutes a novel activation domain (3,8). In addition, RNA splicing leads to production of at least five alternatively spliced isoforms, ␣, ␤, ␥, ⑀, and ␦ (9).It has been shown that mice deficient in p63 are defective in epidermal development, including severe limb malformation and an almost complete absence of mammary glands, skin, teeth, and hair (7, 10, 11). Another study (12) showed that mice heterozygous for p63 are prone to develop an increased tumor burden and metastasis rate, which is compounded in mice harboring heterozygous alleles of p53 and/or p73. Consistent with this, evidence showed that p63, especially ⌬Np63, is found to be amplified and/or overexpressed in multiple tumors and correlated with tumor progression and poor prognosis (13). In addition, overexpression of ⌬Np63 promotes cell proliferation in vitro and tumor growth in vivo (14). These results suggest that TAp63 and ⌬Np63 have opposing functions in tumor suppression. However, somatic mutations of p63 in tumors are rarely detected (15). Thus, the control of p63 activity is likely at the level of p63 expression.DEC1, 2 also named Stra13 (st...

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Section: Discussionsupporting

confidence: 58%

ΔNp63, a Target of DEC1 and Histone Deacetylase 2, Modulates the Efficacy of Histone Deacetylase Inhibitors in Growth Suppression and Keratinocyte Differentiation

Qian

Jung

Chen

2011

Journal of Biological Chemistry

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“…A recent report showed that HDAC inhibitors induced apoptosis in cells of cisplatin-resistant ovarian cancer associated with overexpression of Bad [36] . Moreover, Muscolini et al also reported that an HDAC inhibitor overcome apoptosis resistance to cisplatin by restoring both p73 and Bax [15] . These results demonstrate that HDAC inhibitors overcome resistance to cisplatin by up-regulating the expression of apoptosis-inducing factors.…”

Section: Discussionmentioning

confidence: 99%

“…It was originally isolated from Streptomyces hygroscopicus and identified as a fungistatic antibiotic that inhibits all class I and II HDACs. TSA can alter the expression of 2%-5% of genes [14] and can act as a chemo-sensitizer in cells of ovarian cancer, gastric cancer, and erythroleukemia [15][16][17] . Although the hyperacetylation of histones following inhibition of HDAC activ- [18][19][20][21] , the molecular mechanisms of TSA-sensitized cytotoxicity to chemotherapeutic drugs remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A sensitizes cisplatin-resistant A549 cells to apoptosis by up-regulating death-associated protein kinase

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the apoptosis-inducing effect of trichostatin A (TSA) in the human lung adenocarcinoma cisplatin-resistant cell line (A549/CDDP) and to examine whether TSA can enhance sensitivity to cisplatin treatment and the underlying molecular mechanisms of such an enhancement. Methods: Cell viability was evaluated using the Neutral Red assay. Apoptosis was assessed using Hoechst 33258 staining and flow cytometry analysis. Protein expression was detected by Western blotting. To determine the role of Death-associated protein kinase (DAPK) in TSA-induced apoptosis in the A549/CDDP cell line, cells were transfected with pcDNA3.1(+)-DAPK, which has a higher expression level of DAPK compared to endogenous expression, and DAPK activity was inhibited by both over-expression C-terminal fragment of DAPK which may competitive binding DAPK substrates to inhibit the function of DAPK and RNA interference. Results: TSA induced apoptosis in both A549 cells and A549/CDDP cells. TSA enhanced the sensitivity of A549/CDDP cells to cisplatin, along with concomitant DAPK up-regulation. When DAPK was over-expressed, A549/CDDP cells became sensitive to cisplatin and the cytotoxicity of TSA could be increased. Moreover, the cytotoxicity of TSA could be alleviated by inhibition of DAPK activity by the expression of a recombinant C-terminal fragment of DAPK or RNA interference. Conclusion: TSA induced sensitivity to cisplatin treatment in cisplatin-resistant A549 cells. The up-regulation of DAPK is one of the mechanisms mediating sensitization to TSA-induced apoptosis in cisplatin-resistant cells.

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“…Bax-luciferase reporter construct was obtained by subcloning the PCR-generated fragment (Ϫ715 to Ϫ317 bp) from the bax gene promoter into BglII-HindIII sites of the pGL3-luciferase Enhancer vector (Promega) (19). The HA-tagged ubiquitin (HA-Ub) expression vector, carrying a fusion protein formed by an epitope of the HA and the entire open reading frame of the ubiquitin between the CMV enhancer and promoter and the SV40 polyadenylation signal, has been previously described (27).…”

Section: Methodsmentioning

confidence: 99%

“…This mutation was generated by the substitution AAG/AAT in heterozygosis. Although K351N mutation did not affect p53 expression, it was associated to the acquisition of resistance to apoptosis in A2780 CIS, particularly to defects in both cis-dichlorodiammine platinum (CDDP)-induced Bax expression and associated mitochondrial membrane depolarization, cytochrome c release, and activation of caspase-3 (19). K351N substitution significantly reduced the thermodynamic stability of p53 tetramers without affecting the overall half-life of the protein.…”

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confidence: 91%

The Cancer-associated K351N Mutation Affects the Ubiquitination and the Translocation to Mitochondria of p53 Protein

Muscolini

Montagni

Palermo

et al. 2011

Journal of Biological Chemistry

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Background:A new mutant (K351N) of p53 in the tetramerization domain impairs cisplatin-mediated apoptosis in a cisplatin-resistant ovarian carcinoma cell line. Results: Defects in monoubiquitination of the p53 K351N mutant cause its nuclear accumulation. Conclusion: K351N mutation impairs p53 targeting to mitochondria and transcription-independent apoptosis. Significance: K351N mutation of p53 is critical in contributing to and maintaining the resistance to cisplatin.

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Trichostatin A up-regulates p73 and induces Bax-dependent apoptosis in cisplatin-resistant ovarian cancer cells

Cited by 49 publications

References 47 publications

ΔNp63, a Target of DEC1 and Histone Deacetylase 2, Modulates the Efficacy of Histone Deacetylase Inhibitors in Growth Suppression and Keratinocyte Differentiation

ΔNp63, a Target of DEC1 and Histone Deacetylase 2, Modulates the Efficacy of Histone Deacetylase Inhibitors in Growth Suppression and Keratinocyte Differentiation

Trichostatin A sensitizes cisplatin-resistant A549 cells to apoptosis by up-regulating death-associated protein kinase

The Cancer-associated K351N Mutation Affects the Ubiquitination and the Translocation to Mitochondria of p53 Protein

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