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Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, RunX1T1 in ovarian cancer. Epigenetics 2011 Jun;6(6):727-39

Date

05/05/2011

Pubmed ID

21540640

Pubmed Central ID

PMC3359493

DOI

10.4161/epi.6.6.15856

Scopus ID

2-s2.0-79958741371   23 Citations

Abstract

Aberrant TGFβ signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study has identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGF-beta signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (P=0.035) and in 83% (5/6) of primary ovarian cancer-initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (P< 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFβ/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis.

Author List

Yeh KT, Chen TH, Yang HW, Chou JL, Chen LY, Yeh CM, Chen YH, Lin RI, Su HY, Chen GC, Deatherage DE, Huang YW, Yan PS, Lin HJ, Nephew KP, Huang TH, Lai HC, Chan MW

Author

Yi-Wen Huang PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
DNA Methylation
Epigenesis, Genetic
Female
Gene Silencing
Histones
Humans
Neoplasm Staging
Ovarian Neoplasms
Promoter Regions, Genetic
Proto-Oncogene Proteins
RUNX1 Translocation Partner 1 Protein
Signal Transduction
Transcription Factors
Transforming Growth Factor beta
jenkins-FCD Prod-399 190a069c593fb5498b7fcd942f44b7bc9cdc7ea1