Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer

Michael W Y Chan, Yi Wen Huang, Corinna Hartman-Frey, Chieh Ti Kuo, Daniel Deatherage, Huaxia Qin, Alfred S L Cheng, Pearlly S. Yan, Ramana V. Davuluri, Tim H M Huang, Kenneth Nephew, Huey Jen L Lin

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Abstract

Transforming growth factor-beta (TGF-β)/SMAD signaling is a key growth regulatory pathway often dysregulated in ovarian cancer and other malignancies. Although loss of TGF-β-mediated growth inhibition has been shown to contribute to aberrant cell behavior, the epigenetic consequence(s) of impaired TGF-β/SMAD signaling on target genes is not well established. In this study, we show that TGF-β1 causes growth inhibition of normal ovarian surface epithelial cells, induction of nuclear translocation SMAD4, and up-regulation of ADAM19 (a disintegrin and metalloprotease domain 19), a newly identified TGF-β1 target gene. Conversely, induction and nuclear translocation of SMAD4 were negligible in ovarian cancer cells refractory to TGF-β1 stimulation, and ADAM19 expression was greatly reduced. Furthermore, in the TGF-β1 refractory cells, an inactive chromatin environment, marked by repressive histone modifications (trimethyl-H3K27 and dimethyl-H3K9) and histone dea-cetylase, was associated with the ADAM19 promoter region. However, the CpG island found within the promoter and first exon of ADAM19 remained generally unmethylated. Although disrupted growth factor signaling has been linked to epigenetic gene silencing in cancer, this is the first evidence demonstrating that impaired TGF-β1 signaling can result in the formation of a repressive chromatin state and epigenetic suppression of ADAM19. Given the emerging role of ADAMs family proteins in growth factor regulation in normal cells, we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer.

Original languageEnglish
Pages (from-to)908-919
Number of pages12
JournalNeoplasia
Volume10
Issue number9
DOIs
StatePublished - Sep 2008

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Epigenetic Repression
Disintegrins
Transforming Growth Factors
Metalloproteases
Transforming Growth Factor beta
Ovarian Neoplasms
Epigenomics
Chromatin
ADAM Proteins
Intercellular Signaling Peptides and Proteins
Histone Code
Growth
Neoplastic Processes
CpG Islands
Gene Silencing
Genetic Promoter Regions
Histones
Genes
Exons
Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Chan, M. W. Y., Huang, Y. W., Hartman-Frey, C., Kuo, C. T., Deatherage, D., Qin, H., ... Lin, H. J. L. (2008). Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer. Neoplasia, 10(9), 908-919. https://doi.org/10.1593/neo.08540

Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer. / Chan, Michael W Y; Huang, Yi Wen; Hartman-Frey, Corinna; Kuo, Chieh Ti; Deatherage, Daniel; Qin, Huaxia; Cheng, Alfred S L; Yan, Pearlly S.; Davuluri, Ramana V.; Huang, Tim H M; Nephew, Kenneth; Lin, Huey Jen L.

In: Neoplasia, Vol. 10, No. 9, 09.2008, p. 908-919.

Research output: Contribution to journalArticle

Chan, MWY, Huang, YW, Hartman-Frey, C, Kuo, CT, Deatherage, D, Qin, H, Cheng, ASL, Yan, PS, Davuluri, RV, Huang, THM, Nephew, K & Lin, HJL 2008, 'Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer', Neoplasia, vol. 10, no. 9, pp. 908-919. https://doi.org/10.1593/neo.08540
Chan, Michael W Y ; Huang, Yi Wen ; Hartman-Frey, Corinna ; Kuo, Chieh Ti ; Deatherage, Daniel ; Qin, Huaxia ; Cheng, Alfred S L ; Yan, Pearlly S. ; Davuluri, Ramana V. ; Huang, Tim H M ; Nephew, Kenneth ; Lin, Huey Jen L. / Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer. In: Neoplasia. 2008 ; Vol. 10, No. 9. pp. 908-919.
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AU - Deatherage, Daniel

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AU - Cheng, Alfred S L

AU - Yan, Pearlly S.

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