Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, Runx1T1 in ovarian cancer

Kun Tu Yeh, Tze Ho Chen, Hui Wen Yang, Jian Liang Chou, Lin Yu Chen, Chia Ming Yeh, Yu Hsin Chen, Ru Inn Lin, Her Young Su, Gary C W Chen, Daniel E. Deatherage, Yi Wen Huang, Pearlly S. Yan, Huey Jen Lin, Kenneth Nephew, Tim H M Huang, Hung Cheng Lai, Michael W Y Chan

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 TGFβ 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.

Original languageEnglish
Pages (from-to)727-739
Number of pages13
JournalEpigenetics : official journal of the DNA Methylation Society
Volume6
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

Epigenomics
Ovarian Neoplasms
Methylation
Neoplasms
Carcinogenesis
Histone Code
Cell Line
Histones
Lysine
Epithelial Cells
Maintenance
Growth

Keywords

  • Epigenetics
  • Ovarian cancer
  • RunX1T1
  • TGFβ

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, Runx1T1 in ovarian cancer. / Yeh, Kun Tu; Chen, Tze Ho; Yang, Hui Wen; Chou, Jian Liang; Chen, Lin Yu; Yeh, Chia Ming; Chen, Yu Hsin; Lin, Ru Inn; Su, Her Young; Chen, Gary C W; Deatherage, Daniel E.; Huang, Yi Wen; Yan, Pearlly S.; Lin, Huey Jen; Nephew, Kenneth; Huang, Tim H M; Lai, Hung Cheng; Chan, Michael W Y.

In: Epigenetics : official journal of the DNA Methylation Society, Vol. 6, No. 6, 06.2011, p. 727-739.

Research output: Contribution to journalArticle

Yeh, KT, Chen, TH, Yang, HW, Chou, JL, Chen, LY, Yeh, CM, Chen, YH, Lin, RI, Su, HY, Chen, GCW, Deatherage, DE, Huang, YW, Yan, PS, Lin, HJ, Nephew, K, Huang, THM, Lai, HC & Chan, MWY 2011, 'Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, Runx1T1 in ovarian cancer', Epigenetics : official journal of the DNA Methylation Society, vol. 6, no. 6, pp. 727-739. https://doi.org/10.4161/epi.6.6.15856
Yeh, Kun Tu ; Chen, Tze Ho ; Yang, Hui Wen ; Chou, Jian Liang ; Chen, Lin Yu ; Yeh, Chia Ming ; Chen, Yu Hsin ; Lin, Ru Inn ; Su, Her Young ; Chen, Gary C W ; Deatherage, Daniel E. ; Huang, Yi Wen ; Yan, Pearlly S. ; Lin, Huey Jen ; Nephew, Kenneth ; Huang, Tim H M ; Lai, Hung Cheng ; Chan, Michael W Y. / Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, Runx1T1 in ovarian cancer. In: Epigenetics : official journal of the DNA Methylation Society. 2011 ; Vol. 6, No. 6. pp. 727-739.
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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 TGFβ 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.",
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AU - Chou, Jian Liang

AU - Chen, Lin Yu

AU - Yeh, Chia Ming

AU - Chen, Yu Hsin

AU - Lin, Ru Inn

AU - Su, Her Young

AU - Chen, Gary C W

AU - Deatherage, Daniel E.

AU - Huang, Yi Wen

AU - Yan, Pearlly S.

AU - Lin, Huey Jen

AU - Nephew, Kenneth

AU - Huang, Tim H M

AU - Lai, Hung Cheng

AU - Chan, Michael W Y

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