Promoter Hypomethylation of EpCAM-Regulated Bone Morphogenetic Protein Gene Family in Recurrent Endometrial Cancer

• Published in: Clinical cancer research Vol. 19; no. 22; pp. 6272 - 6285
• Main Authors: Hsu, Ya-Ting, Gu, Fei, Huang, Yi-Wen, Liu, Joseph, Ruan, Jianhua, Huang, Rui-Lan, Wang, Chiou-Miin, Chen, Chun-Liang, Jadhav, Rohit R., Lai, Hung-Cheng, Mutch, David G., Goodfellow, Paul J., Thompson, Ian M., Kirma, Nameer B., Huang, Tim Hui-Ming
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2013
• Subjects: Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antineoplastic agents; Base Sequence; Biological and medical sciences; Bone Morphogenetic Proteins - genetics; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; CpG Islands - genetics; Disease-Free Survival; DNA Methylation; Endometrial Neoplasms - genetics; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; Epithelial Cell Adhesion Molecule; Epithelial-Mesenchymal Transition - drug effects; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Recurrence, Local - genetics; Pharmacology. Drug treatments; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering; Sequence Analysis, DNA; Survival; Transcriptional Activation - drug effects; Tumors; Promoter; Endometrium cancer; Relapse; Bone morphogenetic protein; Uterine diseases; Multigene family; Malignant tumor; Methylation; Cancer; Female genital diseases
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-1734

Purpose: Epigenetic regulation by promoter methylation plays a key role in tumorigenesis. Our goal was to investigate whether altered DNA methylation signatures associated with oncogenic signaling delineate biomarkers predictive of endometrial cancer recurrence. Experimental Design: Methyl-CpG-capture sequencing was used for global screening of aberrant DNA methylation in our endometrial cancer cohort, followed by validation in an independent The Cancer Genome Atlas (TCGA) cohort. Bioinformatics as well as functional analyses in vitro, using RNA interference (RNAi) knockdown, were performed to examine regulatory mechanisms of candidate gene expression and contribution to aggressive phenotype, such as epithelial–mesenchymal transition (EMT). Results: We identified 2,302 hypermethylated loci in endometrial tumors compared with control samples. Bone morphogenetic protein (BMP) family genes, including BMP1, 2, 3, 4, and 7, were among the frequently hypermethylated loci. Interestingly, BMP2, 3, 4, and 7 were less methylated in primary tumors with subsequent recurrence and in patients with shorter disease-free interval compared with nonrecurrent tumors, which was validated and associated with poor survival in the TCGA cohort (BMP4, P = 0.009; BMP7, P = 0.007). Stimulation of endometrial cancer cells with epidermal growth factor (EGF) induced EMT and transcriptional activation of these genes, which was mediated by the epithelial cell adhesion molecule (EpCAM). EGF signaling was implicated in maintaining the promoters of candidate BMP genes in an active chromatin configuration and thus subject to transcriptional activation. Conclusions: Hypomethylation signatures of candidate BMP genes associated with EpCAM-mediated expression present putative biomarkers predictive of poor survival in endometrial cancer. Clin Cancer Res; 19(22); 6272–85. ©2013 AACR.