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

Ye, Cai Guo; Chen, George G.; Ho, Raymond H.; Merchant, Juanita L.; He, Ming; Lai, Paul B.S.

doi:10.1016/j.bbamcr.2013.08.001

Cited by 17 publications

(19 citation statements)

References 33 publications

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“…We found that ZBP-89 inhibited the expression of HDAC3 and pHDAC3 proteins but not HDAC4 (Figure 1 a), confirming our previous finding [ 2 ]. ZBP-89 also did not affect the expression of pHDAC4 protein (Additional file 1 : Figure S1).…”

Section: Resultssupporting

confidence: 91%

“…In this study, we first confirmed our previous finding that ZBP-89 reduced both HDAC3 and pHDAC3 proteins in HCC cells [ 2 ]. The level of HDAC3 is frequently increased in HCC [ 5 - 7 ], suggesting a possible role of HDAC3 in hepatocarcinogenesis.…”

Section: Discussionsupporting

confidence: 89%

“…ZBP-89 regulated expression can result in altered cell growth and death. Previously, we found that ZBP-89 could bind to histone deacetylase 3 (HDAC3) protein to inhibit its deacetylation activity, leading to the increase of pro-apoptotic Bak protein expression in hepatocellular carcinoma (HCC) [ 1 , 2 ]. HDAC3, a histone deacetylase enzyme, removes acetyl-residues from histones and forms transcriptional co-repressors with other proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the level of HDAC3 is regulated by competition between Pin1 and 14-3-3 proteins. Our previous study has shown that ZBP-89 could bind to HDAC3 protein to inhibit its deacetylation activity in HCC [ 2 ]. Thus it appears that HDAC3 is subjected to the control by both ZBP-89 and Pin1.…”

Section: Introductionmentioning

confidence: 99%

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ZBP-89 reduces histone deacetylase 3 by degrading IkappaB in the presence of Pin1

Liu

Chen

et al. 2015

J Transl Med

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BackgroundHistone deacetylase 3 (HDAC3) is overexpressed in cancers and its inhibition enhances anti-tumor chemotherapy. ZBP-89, a transcription factor, can induce pro-apoptotic Bak and reduce HDAC3 but the mechanism is unknown. Pin1, a molecular switch that determines the fate of phosphoproteins, is known to interact with HDAC3. The aim of this study was to investigate the mechanism how ZBP-89 downregulated HDAC3.MethodsIn this study, liver cells, Pin1-knockout Pin1−/− and Pin1 wild-typed Pin+/+ cells were used to explore how ZBP-89 reduced HDAC3. The overexpression of ZBP-89 was achieved by infecting cells with Ad-ZBP-89, an adenoviral construct containing ZBP-89 gene. The role of NF-κB was determined using CAY10576, MG132 and SN50, the former two being inhibitors of IκB degradation and SN50 being an inhibitor of p65/p50 translocation. A xenograft tumor model was used to confirm the in vitro data.ResultsZBP-89 reduced HDAC3, and it could form a complex with IκB and induce IκB phosphorylation to inhibit IκB. Furthermore, ZBP-89-mediated HDAC3 reduction was suppressed by IκB degradation inhibitors CAY10576 and MG132 but not by p65/p50 translocation inhibitor SN50, indicating that IκB decrease rather than the elevated activity of NF-κB contributed to HDAC3 reduction. ZBP-89-mediated HDAC3 or IκB reduction was significantly less obvious in Pin1−/− cells compared with Pin1+/+ cells. In Ad-ZBP-89-infected Pin1+/+ cancer cells, Pin1 siRNA increased HDAC3 but decreased Bak, compared with cells without ZBP-89 infection. These findings indicate that Pin1 participates in ZBP-89-mediated HDAC3 downregulation and Bak upregulation. The cell culture result was confirmed by in vivo mouse tumor model experiments.ConclusionsZBP-89 attenuates HDAC3 by increasing IκB degradation. Such attenuation is independent of NF-κB activity but partially depends on Pin1. The novel pathway identified may help generate new anti-cancer strategy by targeting HDAC3 and its related molecules.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0382-7) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ZBP-89 reduces histone deacetylase 3 by degrading IkappaB in the presence of Pin1

Liu

Chen

et al. 2015

J Transl Med

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“…[11] It plays a significant role in the regulation of cell growth, apoptosis, and carcinogenesis in many types of cancer. [12] But its role and mechanism in CRC is still unclear. [13] Topoisomerases are nuclear enzymes, which regulate DNA topology by action on the temporary cleavage and ligation cycle of DNA.…”

Section: Introductionmentioning

confidence: 99%

ZNF148 modulates TOP2A expression and cell proliferation via ceRNA regulatory mechanism in colorectal cancer

Xian

Liu

et al. 2017

Medicine

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Background:Competing endogenous RNA (ceRNA) regulation is a novel hypothesized mechanism that states RNA molecules share common target microRNAs (miRNAs) and may competitively combine into the same miRNA pool.Methods:Zinc finger protein 148 (ZNF148) and TOP2A expression were analyzed in 742 colorectal cancer (CRC) tissues using immunohistochemistry (IHC). ZNF148 mRNA, TOP2A mRNA, miR101, miR144, miR335, and miR365 expression were estimated in 53 fresh frozen CRC tissues by reverse transcription polymerase chain reaction. Mechanisms underpinning ceRNA were examined using bioinformatics, correlation analysis, RNA interference, gene over-expression, and luciferase assays.Results:Protein levels of ZNF148 and TOP2A detected by IHC positively correlated (Spearman correlation coefficient [rs] = 0.431, P < 0.001); mRNA levels of ZNF148 and TOP2A also positively correlated (r = 0.591, P < 0.001). Bioinformatics analysis demonstrated that ZNF148 and TOP2A mRNA had 13 common target miRNAs, including miR101, miR144, miR335, and miR365. Correlation analysis demonstrated that levels of ZNF148 mRNA were negatively associated with levels of miR144, miR335, and miR365. Knockdown and overexpression tests showed that ZNF148 mRNA and TOP2A mRNA regulated each other in HCT116 cells, respectively, but not in Dicer-deficient HCT116 cells. Luciferase assays demonstrated that ZNF148 and TOP2A regulated each other through 3′UTR. Overexpression of ZNF148 mRNA and TOP2A mRNA caused significant downregulation of miR101, miR144, miR335, and miR365 in the HCT116 cells. We also found that knockdown of ZNF148 and TOP2A significantly promoted cell growth, and overexpression of ZNF148 and TOP2A inhibited cell proliferation, which was abrogated in Dicer-deficient HCT116 cells.Conclusion:ZNF148 and TOP2A regulate each other through ceRNA regulatory mechanism in CRC, which has biological effects on cell proliferation.

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Overexpression of modified human TRβ1 suppresses the growth of hepatocarcinoma SK-hep1 cells in vitro and in xenograft models

et al. 2018

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Association studies suggest that TRβ1 functions as a tumor suppressor. Thyroid hormone receptors (TRs) mediate transcriptional responses through a highly conserved DNA-binding domain (DBD). We previously constructed an artificially modified human TRβ1 (m-TRβ1) via the introduction of a 108-bp exon sequence into the corresponding position of the wild-type human TRβ1 (TRβ1) DBD. Studies confirmed that m-TRβ1 was functional and could inhibit the proliferation of breast cancer MDA-MB-468 cells in vitro. To understand the role of m-TRβ1 in liver tumor development, we adopted a gain-of-function approach by stably expressing TRβ (m-TRβ1 and TRβ1) genes in a human hepatocarcinoma cell line, SK-hep1 (without endogenous TRβ), and then evaluated the effects of the expressed TRβ on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. In the presence of 3,5,3-l-triiodothyronine (T3), the expression of TRβ in SK-hep1 cells inhibited cancer cell proliferation and impeded tumor cell migration through the up-regulation of 4-1BB, Caspase-3, and Bak gene expression; down-regulation of Bcl-2 gene expression; and activation of the Caspase-3 protein. TRβ expression in SK-hep1 led to less tumor growth in xenograft models. Additionally, the anti-tumor effect of m-TRβ1 was stronger than that of TRβ1. These data indicate that m-TRβ1 can act as a tumor suppressor in hepatocarcinoma and its role was significantly better than that of TRβ1.

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

Cited by 17 publications

References 33 publications

ZBP-89 reduces histone deacetylase 3 by degrading IkappaB in the presence of Pin1

ZBP-89 reduces histone deacetylase 3 by degrading IkappaB in the presence of Pin1

ZNF148 modulates TOP2A expression and cell proliferation via ceRNA regulatory mechanism in colorectal cancer

Overexpression of modified human TRβ1 suppresses the growth of hepatocarcinoma SK-hep1 cells in vitro and in xenograft models

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