Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer

Ya Ting Hsu, Fei Gu, Yi Wen Huang, Joseph Liu, Jianhua Ruan, Rui Lan Huang, Chiou Miin Wang, Chun Liang Chen, Rohit R. Jadhav, Hung Cheng Lai, David G. Mutch, Paul J. Goodfellow, Ian M. Thompson, Nameer B. Kirma, Tim Hui Ming Huang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)6272-6285
Number of pages14
JournalClinical Cancer Research
Volume19
Issue number22
DOIs
Publication statusPublished - Nov 15 2013
Externally publishedYes

Fingerprint

Bone Morphogenetic Proteins
Endometrial Neoplasms
Epithelial-Mesenchymal Transition
Atlases
Genes
DNA Methylation
Neoplasms
Epidermal Growth Factor
Transcriptional Activation
Biomarkers
Genome
Recurrence
Survival
RNA Interference
Computational Biology
Epigenomics
Methylation
Chromatin
Carcinogenesis
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer. / 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.

In: Clinical Cancer Research, Vol. 19, No. 22, 15.11.2013, p. 6272-6285.

Research output: Contribution to journalArticle

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, THM 2013, 'Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer', Clinical Cancer Research, vol. 19, no. 22, pp. 6272-6285. https://doi.org/10.1158/1078-0432.CCR-13-1734
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. / Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 22. pp. 6272-6285.
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abstract = "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.",
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T1 - Promoter hypomethylation of EpCAM-regulated bone morphogenetic protein gene family in recurrent endometrial cancer

AU - Hsu, Ya Ting

AU - Gu, Fei

AU - Huang, Yi Wen

AU - Liu, Joseph

AU - Ruan, Jianhua

AU - Huang, Rui Lan

AU - Wang, Chiou Miin

AU - Chen, Chun Liang

AU - Jadhav, Rohit R.

AU - Lai, Hung Cheng

AU - Mutch, David G.

AU - Goodfellow, Paul J.

AU - Thompson, Ian M.

AU - Kirma, Nameer B.

AU - Huang, Tim Hui Ming

PY - 2013/11/15

Y1 - 2013/11/15

N2 - 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.

AB - 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.

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