title: Frequent SOCS3 and 3OST2 promoter methylation and their epigenetic regulation in endometrial carcinoma.
abstract: DNA methylation has been considered as an important means of early diagnosis of cancer, which cooperates with histone modifications, playing a crucial role in silencing tumor suppressor genes (TSGs). However, how TSGs are regulated by these epigenetic mechanisms in cancer remains unknown. In this study, we first evaluated 7 TSGs methylation in the early diagnosis of endometrial carcinoma (EC), and then explored the epigenetic mechanisms of their transcriptional regulation. The results showed that SOCS3 and 3OST2 were the most frequently methylated genes in EC (88.3% and 78.3%, respectively), and 3OST2 was correlated with younger patients (< 57 years, P = 0.030) and well-differentiated EC (P = 0.026). Unlike 3OST2, SOCS3 methylation occurred even in complex hyperplasia (53.3%) and atypical hyperplasia (54.2%). 5-aza-2'-deoxycytidine (5-Aza-CdR) or trichostatin A (TSA) alone could partially reverse SOCS3 and 3OST2 methylation, and their combination completely reversed the methylation of both genes. In addition, UHRF1 and methylated H3R8 were enriched on both hypermethylated SOCS3 and 3OST2 promoters, but after 5-Aza-CdR or TSA treatment, the UHRF1 and H3R8me2s enrichment was decreased while H3R8me2a enrichment was increased. In conclusion, we demonstrate for the first time that SOCS3 and 3OST2 methylation plays an important role in endometrial carcinogenesis, and could be directly regulated by UHRF1. Moreover, H3R8me2s acts as a repressive mark, while H3R8me2a was correlated with transcriptional activity in EC.
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China ; Department of Pathology, Shandong Provincial Chest Hospital Jinan 250012, P R China.
authors: Haiyan
authors: H
authors: Chen
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China.
authors: Cuijuan
authors: C
authors: Zhang
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China.
authors: Yan
authors: Y
authors: Sheng
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China.
authors: Shuzhe
authors: S
authors: Yao
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China.
authors: Zhiyan
authors: Z
authors: Liu
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China.
authors: Cheng
authors: C
authors: Zhang
authors: Institute of Pathology and Pathophysiology, Shandong University School of Medicine Jinan 250012, P R China.
authors: Tingguo
authors: T
authors: Zhang
keywords: DNA methylation; Endometrial carcinoma; gene expression; histone modifications; tumor suppressor genes
references: Recent Pat Anticancer Drug Discov. 2011 Jan;6(1):116-30
references: 21110828
references: J Clin Oncol. 2006 Oct 10;24(29):4783-91
references: 17028294
references: J Biol Chem. 1999 Feb 19;274(8):5185-92
references: 9988768
references: Mol Cancer Ther. 2006 Jan;5(1):8-19
references: 16432158
references: Mol Cell Biol. 2004 Nov;24(21):9630-45
references: 15485929
references: Am J Cancer Res. 2011;1(3):413-418
references: 21969221
references: Mol Cell. 2005 Apr 29;18(3):263-72
references: 15866169
references: Clin Cancer Res. 2009 Sep 15;15(18):5772-83
references: 19723644
references: Gut. 2010 Nov;59(11):1516-26
references: 20947886
references: Oncol Rep. 2012 Dec;28(6):1997-2002
references: 23023523
references: Cancer Res. 2008 Jun 15;68(12 ):4597-605
references: 18559504
references: Nature. 2008 Oct 9;455(7214):818-21
references: 18772891
references: Epigenomics. 2010 Jun;2(3):419-47
references: 22121902
references: J Biol Chem. 2013 Jan 11;288(2):1329-39
references: 23161542
references: J Cell Mol Med. 2013 Oct;17(10):1282-90
references: 24131863
references: Mol Cell. 2011 Jul 22;43(2):275-84
references: 21777816
references: Mol Cell Biol. 2011 Oct;31(19):4119-28
references: 21791605
references: Int J Cancer. 2008 Jul 15;123(2):296-302
references: 18404674
references: Oncogene. 2008 Jun 5;27(25):3615-23
references: 18223691
references: Breast Cancer Res Treat. 2010 Nov;124(1):39-48
references: 20037778
references: Hepatology. 2012 Sep;56(3):994-1003
references: 22407776
references: Clin Cancer Res. 2004 Aug 1;10(15):5131-6
references: 15297416
references: Int J Oncol. 2010 May;36(5):1201-8
references: 20372794
references: Gynecol Oncol. 2007 Oct;107(1):143-53
references: 17692907
references: Front Biosci. 2006 Jan 01;11:344-55
references: 16146736
references: Mol Cell Biol. 2008 Jan;28(2):705-17
references: 17967883
references: Carcinogenesis. 2003 Aug;24(8):1337-45
references: 12807730
references: Nucleic Acids Res. 2013 Mar 1;41(5):2797-806
references: 23345616
references: EMBO Rep. 2009 Nov;10(11):1259-64
references: 19798101
references: Am J Cancer Res. 2014 Sep 06;4(5):508-17
references: 25232492
references: Adv Genomics Genet. 2012 Mar;2012(2):33-47
references: 22888282
references: Nature. 2008 Oct 9;455(7214):826-9
references: 18772888
references: Pharmacol Ther. 2007 Sep;115(3):419-34
references: 17658611
references: Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):12950-5
references: 22837395
references: Nature. 2008 Oct 9;455(7214):822-5
references: 18772889
references: Biochem Biophys Res Commun. 2009 Dec 18;390(3):523-8
references: 19800870
references: Nucleic Acids Res. 2009 Feb;37(2):493-505
references: 19056828
references: J Gastroenterol. 2013 Jan;48(1):132-43
references: 22766745
references: Oncogene. 2004 Oct 7;23(46):7601-10
references: 15361834
references: Int J Cancer. 2006 May 1;118(9):2168-71
references: 16331610
references: Mol Cancer Res. 2007 Sep;5(9):873-80
references: 17704140