Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer. Clin Cancer Res 2013 Nov 15;19(22):6272-85
Date
10/01/2013Pubmed ID
24077349Pubmed Central ID
PMC4080631DOI
10.1158/1078-0432.CCR-13-1734Scopus ID
2-s2.0-84888082619 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
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.
Author List
Hsu YT, Gu F, Huang YW, Liu J, Ruan J, Huang RL, Wang CM, Chen CL, Jadhav RR, Lai HC, Mutch DG, Goodfellow PJ, Thompson IM, Kirma NB, Huang THMESH terms used to index this publication - Major topics in bold
Antigens, NeoplasmBase Sequence
Bone Morphogenetic Proteins
Cell Adhesion Molecules
Cell Line, Tumor
CpG Islands
DNA Methylation
Disease-Free Survival
Endometrial Neoplasms
Epidermal Growth Factor
Epithelial Cell Adhesion Molecule
Epithelial-Mesenchymal Transition
Female
Humans
Neoplasm Recurrence, Local
Promoter Regions, Genetic
RNA Interference
RNA, Small Interfering
Sequence Analysis, DNA
Survival
Transcriptional Activation