A CCRK-EZH2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients

Feng, Hai; Yu, Zhuo; Tian, Yuan; Lee, Ying‐Ying; Li, May S.; Go, Minnie Y.Y.; Cheung, Yu‐San; Lai, Paul Bs; Chan, Andrew M.; To, Ka‐Fai; Chan, Henry Lik‐Yuen; Sung, Joseph J.Y.; Cheng, Alfred S.L.

doi:10.1016/j.jhep.2014.11.040

Cited by 64 publications

(65 citation statements)

References 34 publications

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“…Being a key member of the Drosophila Polycomb group (PcG), EZH2 plays a crucial role in gene expression regulation, maintenance of cell identity, stem cell renewal and oncogenesis. Recent studies have shown that EZH2 overexpression predicts poor patient prognosis and is a frequent event in various cancers, such as breast cancer [1], malignant prostate cancer [2], and hepatocellular carcinoma [3]. There are reports depicting the expression and oncogenic role of EZH2 in lung tumorigenesis [4,5] and EZH2 has been suggested to modulate several pathophysiological processes by promoting cell proliferation and cell cycle progression [6], accelerating cell infiltration and metastasis [7], and inhibiting apoptosis [8].…”

Section: Introductionmentioning

confidence: 99%

EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer

Geng¹,

Li²,

Zhou³

et al. 2015

Cancer Letters

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Section: Introductionmentioning

confidence: 99%

EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer

Geng¹,

Li²,

Zhou³

et al. 2015

Cancer Letters

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“…35, 36 Furthermore, EZH2 and AKT could influence expression of each other indicating that they constituted a positive loop. 21, 37, 38, 39 In addition, one-fifth of all human lncRNAs identified is physically associated with EZH2. 18, 19 Here, gain and loss of UCA1 assay in GC cell has been performed.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer

et al. 2017

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Long noncoding RNA UCA1 has emerged as a novel regulator in cancer initiation and progression of various cancers. However, function and underlying mechanism of UCA1 in the progression of gastric cancer (GC) remain unclear. In the present study, we report that UCA1 expressed highly in GC tissues and GC cells, which was partly induced by SP1. UCA1 promoted GC cell proliferation and G1/S transition in vitro and in vivo. Moreover, UCA1 exerted its function through interacting with EZH2, promoting direct interaction with cyclin D1 promoter to activate the translation of cyclin D1. Furthermore, AKT/GSK-3B/cyclin D1 axis was activated to upregulate cyclin D1 due to overexpression of UCA1. In addition, EZH2 and phosphorylated AKT induced by UCA1 could impact each other to form a positive feedback to promote cyclin D1 expression. This study demonstrated that UCA1 as a critical regulator involved in GC proliferation and cell cycle progression by promoting cyclin D1 expression, which indicates that it may be clinically a potential therapeutic target in GC.

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“…Lentiviruses encoding shRNA against Hdac8 (shHdac8) or control sequence (shCtrl) were packaged according to the manufacturer's instructions (Dharmacon) for transduction in the dietary obesity models. At the age of 6 and 18 weeks, 5 Â 10 7 transducing units of lentiviruses in 100 mL PBS were administered via tail vein injection as previously described (17,18). Intraperitoneal glucose or insulin tolerance test (IPGTT/IPITT) was performed at the age of 26 weeks.…”

Section: Lentiviral-mediated Shrna Knockdown In Obesity-promoted Nashmentioning

confidence: 99%

Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma

et al. 2015

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The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesitypromoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLDassociated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G 2 -M phase cell-cycle arrest and stimulated b-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active b-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients. Cancer Res; 75(22); 4803-16. Ó2015 AACR.

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A CCRK-EZH2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients

Abstract: These findings uncover an epigenetic vicious cycle in hepatocarcinogenesis that operates through reciprocal regulation of CCRK and EZH2, providing novel therapeutic strategy for HCC.

Cited by 64 publications

References 34 publications

EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer

EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer

Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer

Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma

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