Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2
Authors: Lin Chen
Jianxin Gu
Heng Zhang
Yu Zhu
Deng Pan
Hongyong He
Weisi Liu
Yidong Liu
Shanshan Wang
Jiejie Xu
Le Xu
Qian Wu
Jing Liu
Haiou Liu
Journal: Cancer Science (2013)
Discipline: CLINICAL MEDICINE
Keywords: EZH2; hepatocellular carcinoma; sorafenib; histone methyltransferase; proteasome-mediated degradation
Affiliations: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai, China., Department of Urology; Zhongshan Hospital; Shanghai Medical College; Fudan University; Shanghai; China, Department of General Surgery; Zhongshan Hospital; Shanghai Medical College; Fudan University; Shanghai; China, School of Medicine; Nantong University; Nantong; China, Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Shanghai; China

Abstract:  Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes that regulate cancer cell growth and survival. It is overexpressed in hepatocellular carcinoma (HCC) with a clinical significance that remains obscure. Sorafenib, a multikinase inhibitor, has been used as a first-line therapeutic drug and shown clinical efficiency for advanced-stage HCC patients. In the present study, we found that sorafenib lowered the protein level of EZH2 through accelerating proteasome-mediated EZH2 degradation in hepatoma cells. Overexpression of EZH2 reversed sorafenib-induced cell growth arrest, cell cycle arrest, and cell apoptosis dependent on histone methyltransferase activity in hepatoma cells. More importantly, shRNA-mediated EZH2 knockdown or EZH2 inhibition with 3-deazaneplanocin A treatment promoted sorafenib-induced hepatoma cell growth arrest and apoptosis. Sorafenib altered the hepatoma epigenome by reducing EZH2 and H3K27 trimethylation. These results revealed a novel therapeutic mechanism underlying sorafenib treatment in suppressing hepatoma growth and survival by accelerating EZH2 degradation. Genetic deletion or pharmacological ablation of EZH2 made hepatoma cells more sensitive to sorafenib, which helps provide a strong framework for exploring innovative combined therapies for advanced-stage HCC patients. 

Retracted: No

PubPeer comments:
 Partial data duplication for winter wheat crop years 2010 2011, 2011 2012, 2012 2013, and 2013 2014 in Table 2 of both papers (first 5 columns) (total = 20 data points). 2018 = https: doi.org 10.34101 actaagrar 150 1732 2017 = DOI: 10.18380 SZIE.COLUM.2017.4.1.59 (cannot link to PubPeer) http: www.columella.mkk.szie.hu archives columella_7_2017 Pepo_Columella_vol4no1(2017)_59-64.pdf Even though the 2017 paper is cited in the 2018 paper, the 2018 paper does not indicate this duplication in data and displays the 2017 paper in the introduction, as follows (p. 358): u201cbut the crop rotation, irrigation, plant density, weed control (Berzsenyi et al., 2000; Vad et al., 2007; Pepu00f3, 2017) have important role, too.u201d , 
 Partial data duplication for winter wheat cultivars GK u00d6thalom, Pannonikus, Euclide, GK Csillag, Bitop, and GK Bu00e9ku00e9s in Figure 1 (maximum yield; 2012 paper) and Table 1 u2013 2012 year (2018 paper). 2012 = https: doi.org 10.34101 actaagrar 49 2534 2018 = https: doi.org 10.34101 actaagrar 150 1732 The 2012 paper is not cited in the 2018 paper. ,