Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma

Zhang, Chris Z.Y.; Chen, George G.; Merchant, Juanita L.; Lai, Paul B.S.

doi:10.4161/cc.11.2.18758

Cited by 14 publications

(18 citation statements)

References 40 publications

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“…10 µM of each ZBP-89 siRNA, HDAC3 siRNA, or DNMT1 siRNA were transfected into the cells with Fugene reagent (Roche, Indianapolis, IN). The replication-deficient recombinant adenoviral expression vector Ad-ZBP-89 was used according to previous publications [3,5]. …”

Section: Methodsmentioning

confidence: 99%

“…These experiments were performed according to the previous publications [3,5]. Briefly, cell lysates were incubated overnight with primary antibody after being precleared with protein A/G PLUS-agarose beads.…”

Section: Methodsmentioning

confidence: 99%

“…The immunohistochemical examination was carried out according to our previous publication [3,5]. Briefly, the tissue sections were incubated with a primary antibody followed by a HRP-labeled IgG secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to its ability to bind to gene promoters, ZBP-89 also forms protein-protein interactions 2 . For example, ZBP-89 interacts with histone deacetylases (HDAC) to repress p16 and vimentin gene transcription [2,4], or interacts with p53, GATA-1 and/or FOG-1 to activate gene expression [5,6]. These studies propose a link between ZBP-89 and epigenetic regulation, though the detailed mechanism is not understood.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma

Chen

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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ZBP-89 regulates Bak to facilitate apoptosis in cancer cells. This study examined if ZBP-89 regulates Bak through an epigenetic mechanism in hepatocellular carcinoma (HCC). We first demonstrated that the expression of Bak was reduced but the levels of DNMT1 and HDAC3 were increased in HCC cancer tissues compared to the corresponding non-cancer tissues. Moreover, there was a negative correlation between Bak expression and DNMT1 levels in HCC. Administration of ZBP-89 downregulated HDAC3 expression and suppressed the activities of HDAC and DNMT, which led to maintenance of histone acetylation status, inhibited the binding of methyl-CpG-binding protein 2 to genomic DNA and demethylated CpG islands in the Bak promoter in HCC cells. Using the xenograft mouse tumor model, we demonstrated that ZBP-89 or inhibitors of either epigenetic enzymes could stimulate Bak expression, induce apoptosis, and arrest tumor growth and that the maximal effort was achieved when ZBP-89 and the enzyme inhibitors was used in combination. Conclusively, ZBP-89 upregulates the expression of Bak by targeting multiple components of the epigenetic pathway in HCC.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma

Chen

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…qRT-PCR and western blot analyses were performed according to our previous study (Zhang et al, 2012). The sequences of the PCR primers were as follows: TRIM65, forward: 5′-CCTTCCATGCCCTCTTCAAC-3′ and reverse: 5′-CTCCATCCCATGCCTTCTTC-3′; β-actin, forward: 5′-TGG-CACCCAGCACAATGAA-3′ and reverse: 5′-CTAAGTCATAGTCCGC-CTAGAAGCA-3′.…”

Section: Qrt-pcr and Western Blot Analysismentioning

confidence: 99%

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Yang

Zhang

Qing

et al. 2017

Journal of Cell Science

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Deregulation of ubiquitin ligases contributes to the malignant progression of human cancers. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcome in two independent cohorts containing 888 patients. In vitro and in vivo data demonstrated that overexpression of TRIM65 promoted cell growth and tumor metastasis, whereas knockdown of TRIM65 resulted in opposite phenotypes. Further studies revealed that TRIM65 exerted oncogenic activities via ubiquitylation of Axin1 to activate the β-catenin signaling pathway. TRIM65 directly bound to Axin1 and accelerated its degradation through ubiquitylation. Furthermore, HMGA1 was identified as an upstream regulator of TRIM65 in HCC cells. In clinical samples, TRIM65 expression was positively correlated with the expression of HMGA1 and nuclear β-catenin. Collectively, our data indicate that TRIM65 functions as an oncogene in HCC. The newly identified HMGA1/TRIM65/β-catenin axis serves as a promising prognostic factor and therapeutic target.

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Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma

Liu

Chen

et al. 2016

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality in part due to its high resistance to chemotherapeutic drugs. The anti-apoptotic Mcl-1 expression has been reported as a resistance factor in various types of tumors. Here, we investigated the expression of Mcl-1 in hepatoma cells and HCC tissues and its relationship with p53, and analyzed the possibility of the gene as a molecular target for HCC therapy. HCC specimens of 30 patients were examined by immunohistochemistry for Mcl-1 and p53 expression. Mcl-1 expression in hepatoma cell lines was measured by RT-PCR and Western blotting. The suppression of Mcl-1 by RNA interference or specific phosphatidylinositol-3 kinase (PI3K) inhibitor, LY294002, was evaluated as monotherapy, and it was combined with mitomycin C (MMC) in treating hepatoma cell line HepG2. Cell viability and apoptosis were assessed by MTT and FACS analysis. Finally, changes of Mcl-1 or p53 expression in various hepatoma cell lines were examined after transfection with Mcl-1 siRNA, the Mcl-1 expression plasmid, or the wide-type p53 expression plasmid, respectively. Mcl-1 protein was remarkably enhanced in HCC tissues as compared with adjacent non-tumor liver tissues. In addition, Mcl-1 was prominently expressed in HepG2 and Hep3B cells, weakly in SMMC7721 cells, and not in L02 cells. P53 protein was also overexpressed in HCC tissues and there was a significant correlation between the expression of p53 and Mcl-1. Silencing Mcl-1 by RNAi or LY294002 downregulated Mcl-1 expression and led to decreased cell viability and increased apoptosis. Combination of MMC and Mcl-1 RNAi or LY294002 exhibited a significant chemosensitizing effect. The expression of p53 was not influenced by Mcl-1 siRNA in HepG2 cells or transfection with the Mcl-1 expression plasmid in L02 cells. Furthermore, the expression of Mcl-1 in Hep3B cells was also not significantly changed after transfection with the wild-type p53 expression plasmid. It is concluded that Mcl-1 is overexpressed in HCC tissues. The mechanisms by which silencing Mcl-1 sensitizes hepatoma cells towards chemotherapy may be not attributed to the upregulated expression of p53 but the dysfunction of p53 through Mcl-1/p53 interaction. Mcl-1 may be a potential target of gene therapy for HCC.

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Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma

Cited by 14 publications

References 40 publications

Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma

Epigenetic upregulation of Bak by ZBP-89 inhibits the growth of hepatocellular carcinoma

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma

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