The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer
Journal
Annals of Surgical Oncology
Journal Volume
22
Pages
1556-1565
Date Issued
2015
Author(s)
Abstract
Background: Emerging evidence suggests that G9a, a histone methyltransferase, is involved in tumor progression and metastasis. However, the functional significance of G9a in endometrial carcinogenesis has not been defined. Methods: The differential expression of G9a in cancer and normal tissues was assessed using an array of 28 paired samples. Tissue specimens from 94 patients with endometrial cancer who underwent primary surgery were immunohistochemically evaluated for G9a and E-cadherin expression. To assess the biologic role of G9a in endometrial cancer, G9a was either stably knocked down or knocked down using a tetracycline-controllable system in endometrial cancer cells, followed by functional assays. Results: Increased G9a expression was identified in endometrial cancer tissues, and its expression was specifically correlated with deep myometrial invasion. Cell invasiveness was inhibited by an RNAi-mediated knockdown of G9a in invasive endometrial cancer cells in vitro and in vivo. An important mediator of G9a-induced tumor invasion is the epigenetic silencing of E-cadherin. Knockdown of G9a restored E-cadherin expression by reducing H3K9me2 levels and decreasing CDH1 promoter DNA methyltransferase recruitment. Knockdown of RNAi-mediated E-cadherin substantially relieved the invasion suppression imposed by G9a suppression. A significant negative correlation between G9a and E-cadherin expression was observed in endometrial cancer (Spearman’s rho, ?0.27; P?=?0.02). Conclusions: This study provides the first clear evidence that G9a contributes to endometrial cancer progression. Mechanistic investigations suggest that E-cadherin repression mediates the effects of G9a. Targeting G9a-mediated epigenetic pathway dysregulation may be a therapeutic strategy for endometrial cancers. ? 2015, Society of Surgical Oncology.
SDGs
Other Subjects
DNA methyltransferase; histone H3; histone methyltransferase; histone methyltransferase G9a; tetracycline; unclassified drug; uvomorulin; cadherin; EHMT2 protein, human; histocompatibility antigen; histone lysine methyltransferase; tumor marker; adult; Article; cancer surgery; cancer tissue; cell migration; controlled study; correlation analysis; endometrial cancer cell line; endometrium cancer; epigenetics; female; gene repression; gene silencing; human; human cell; immunohistochemistry; immunoreactivity; in vitro study; in vivo study; major clinical study; myometrial invasion; protein analysis; protein expression; protein function; RNA interference; tumor invasion; animal; antagonists and inhibitors; apoptosis; cancer grading; cancer staging; cell motion; cell proliferation; chromatin immunoprecipitation; endometrium tumor; enzyme immunoassay; gene expression regulation; genetic epigenesis; genetics; metabolism; middle aged; mouse; myometrium; nonobese diabetic mouse; pathology; prognosis; promoter region; real time polymerase chain reaction; retrospective study; SCID mouse; survival rate; tumor cell culture; tumor invasion; Western blotting; Animals; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cadherins; Cell Movement; Cell Proliferation; Chromatin Immunoprecipitation; Endometrial Neoplasms; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Humans; Immunoenzyme Techniques; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Myometrium; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; Retrospective Studies; Survival Rate; Tumor Cells, Cultured
Type
journal article