HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA

Fritsche, Petra; Seidler, Barbara; Schüler, Susanne; Schnieke, Angelika; Göttlicher, Martin; Schmid, Roland M.; Saur, Dieter; Schneider, Günter

doi:10.1136/gut.2009.180711

Cited by 149 publications

(148 citation statements)

References 46 publications

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“…Chromatin immunoprecipitation revealed a significantly increased binding of acetylated histone H3 to the ZAG promoter (Figure 3d), suggesting an open chromatin conformation within that region. As it has been shown recently that inhibition of HDAC in Panc-1 cells abolished TGF-b1-mediated EMT (Fritsche et al, 2009;von Burstin et al, 2009) Figure 3e). The changes in CDH1 and VIM expression were also confirmed on the protein level ( Figure 3f).…”

Section: Azgp1 In Pancreatic Cancersupporting

confidence: 59%

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

et al. 2010

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Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-b (TGF-b) signaling leads to aggressive cancer progression. In this study, we identified zinc-a2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-a5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-b signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-b-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-b-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype.

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Section: Azgp1 In Pancreatic Cancersupporting

confidence: 59%

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

et al. 2010

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“…HDAC2 interacts with Snail to exert transcriptional repression of E-cadherin and the promotion of tumor metastasis (19,44). HDAC2 confers resistance to etoposide in pancreatic cancer cells by activating BH3-only NOXA (45). In our data, HDAC2 interacts with Snail in Malme3M R cells (Fig.…”

Section: Discussionsupporting

confidence: 60%

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

Kim

Park

et al. 2010

Journal of Biological Chemistry

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The role of the cancer/testis antigen CAGE in drug resistance was investigated. The drug-resistant human melanoma Malme3M (Malme3M R ) and the human hepatic cancer cell line SNU387 (SNU387 R ) showed in vivo drug resistance and CAGE induction. Induction of CAGE resulted from decreased expression and thereby displacement of DNA methyltransferase 1(DNMT1) from CAGE promoter sequences. Various drugs induce expression of CAGE by decreasing expression of DNMT1, and hypomethylation of CAGE was correlated with the increased expression of CAGE. Down-regulation of CAGE in these cell lines decreased invasion and enhanced drug sensitivity resulting from increased apoptosis. Down-regulation of CAGE also led to decreased anchorage-independent growth. Down-regulation of CAGE led to increased expression of p53, suggesting that CAGE may act as a negative regulator of p53. Down-regulation of p53 enhanced resistance to drugs and prevented drugs from exerting apoptotic effects. In SNU387 R cells, CAGE induced the interaction between histone deacetylase 2 (HDAC2) and Snail, which exerted a negative effect on p53 expression. Chromatin immunoprecipitation assay showed that CAGE, through interaction with HDAC2, exerted a negative effect on p53 expression in Malme3M R cells. These results suggest that CAGE confers drug resistance by regulating expression of p53 through HDAC2. Taken together, these results show the potential value of CAGE as a target for the development of cancer therapeutics.

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“…Increasing evidence has revealed that HDAC2 is often overexpressed in various types of tumors (10)(11)(12)(13)(14)(15). In addition, the ablation of HDAC2 markedly inhibits tumor growth and induces apoptosis (13,14,16), suggesting HDAC2 functions as oncogene in these tumors. Most importantly, monitoring HDAC2 expression during treatment can act as a marker for the efficacy of HDAC inhibitors (HDACis), and thus the HDAC2 level represents an independent prognostic marker in the clinic (17,18).…”

Section: Introductionmentioning

confidence: 99%

HDAC2 regulates cell proliferation, cell cycle progression and cell apoptosis in esophageal squamous cell carcinoma EC9706 cells

Wang

et al. 2016

Oncology Letters

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Abstract.Increasing evidence has demonstrated that histone deacetylase 2 (HDAC2) participates in the regulation of a variety of biological processes in numerous tumors. However, the potential role of HDAC2 in the development and progression of esophageal squamous cell carcinoma (ESCC) remains elusive. Immunohistochemistry was utilized to detect the expression of HDAC2, Cell Counting Kit-8 was used to determine the cell proliferation, and flow cytometry was employed to investigate cell cycle and cell apoptosis. Finally, western blotting was employed to detect the protein expression of cyclin D1, p21, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). The present study found that expression of HDAC2 protein in ESCC tissues was significantly increased compared with atypical hyperplasia tissues and normal esophageal mucosa (P<0.001). The expression of HDAC2 was not associated with the age or gender of patients (P>0.05), but was closely associated with the histological grade, invasion depth, tumor-node-metastasis stage and lymph node metastasis, respectively (all P<0.001). HDAC2 small interfering RNA effectively downregulated the expression of HDAC2 protein in ESCC EC9706 cells. Downregulation of HDAC2 expression evidently inhibited cell proliferation, arrested cell cycle at the G0/G1 phase and induced cell apoptosis in ESCC EC9706 cells, coupled with increased expression of p21 and Bax proteins and decreased expression of cyclin D1 and Bcl-2 proteins. Overall, the present findings suggest that HDAC2 may play an important role in the development and progression of ESCC and be considered as a novel molecular target for the treatment of ESCC.

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HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA

Cited by 149 publications

References 46 publications

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

Cancer/Testis Antigen CAGE Exerts Negative Regulation on p53 Expression through HDAC2 and Confers Resistance to Anti-cancer Drugs

HDAC2 regulates cell proliferation, cell cycle progression and cell apoptosis in esophageal squamous cell carcinoma EC9706 cells

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