Histone deacetylase 3 promotes pancreatic cancer cell proliferation, invasion and increases drug-resistance through histone modification of P27, P53 and Bax

Jiao, Feng; Hu, Hai; Yuan, Cuncun; Jin, Ziliang; Guo, Zhen; Wang, Liwei; Wang, Lei

doi:10.3892/ijo.2014.2568

Cited by 40 publications

(34 citation statements)

References 31 publications

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“…Inhibition of HDAC3 activity by MI192 was subsequently assessed by evaluating specific acetylation of histone H3, the downstream target of HDAC3. 21 We found that MI192 increased specific histone H3 acetylation, and HDAC3 overexpression reversed this effect (Figures 4a, b and d). …”

Section: Resultsmentioning

confidence: 67%

“…We investigated the effects of HDAC3 on their downstream targets following MI192 treatment, including acetylated α -histone3, P53 and Bax. 21 MI192-induced caspase substrate (polyADP ribose polymerase (PARP) and caspase-3) cleavage and P53 expression were mimicked by HDAC3 knockdown (Figures 3d and e). Altogether, these results indicate that HDAC3 participated in MI192-induced apoptosis in CCA cells and that HDAC3 might be the target of MI192.…”

Section: Resultsmentioning

confidence: 99%

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Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

et al. 2017

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Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochemistry showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

et al. 2017

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“…The related TBLR1 acts as a co-activator to repress prostate cancer proliferation via the androgen receptor (AR) [90]. Jiao et al reported that HDAC3 was upregulated in human pancreatic cancer and depletion of HDAC3 decreased the cell proliferation in vitro [91].…”

Section: The Gps2 Subunit Of the Hdac3 Co-repressor Complexmentioning

confidence: 99%

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

Fan

Toubal

Goñi

et al. 2016

Nat Med

135

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Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.

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“…Overexpression of HDAC3 has been reported in numerous cancer types, such as lung, colorectal, and gastric cancer, as well as in prostate cancer. Currently, there is increasing interest in HDAC3 as a promising therapeutic target in multiple myeloma, leukemia, and gastric cancer …”

Section: Expression Of Hdacs In Cancersmentioning

confidence: 99%

Histone deacetylases function as novel potential therapeutic targets for cancer

Zhang

Shang

Chen

et al. 2016

Hepatology Research

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Diverse cellular functions, including tumor suppressor gene expression, DNA repair, cell proliferation and apoptosis, are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) are enzymes involved in remodeling of chromatin by deacetylating the lysine residues. They play a pivotal role in epigenetic regulation of gene expression. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation have been implicated in the pathogenesis of various diseases, including cancer. Histone deacetylases have become a target for the development of drugs for treating cancer because of their major contribution to oncogenic cell transformation. Overexpression of HDACs correlates with tumorigenesis. Previous work showed that inhibition of HDACs results in apoptosis and the inhibition of cell proliferation in multiple cells. A significant number of HDAC inhibitors have been developed in the past decade. These inhibitors have strong anticancer effects in vitro and in vivo, inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. In addition, HDAC-mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c-Myc, and nuclear factor-κB, as well as the extracellular signal-regulated kinase1/2, phosphatidylinositol 3-kinase, Notch, and Wnt signaling pathways. This review highlights the role of HDACs in cancer pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.

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Histone deacetylase 3 promotes pancreatic cancer cell proliferation, invasion and increases drug-resistance through histone modification of P27, P53 and Bax

Cited by 40 publications

References 31 publications

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

Histone deacetylases function as novel potential therapeutic targets for cancer

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