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 language | English (US) |
|---|---|
| Pages (from-to) | 908-919 |
| Number of pages | 12 |
| Journal | Neoplasia |
| Volume | 10 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2008 |
Funding
Abbreviations: ADAM19, a disintegrin and metalloprotease domain 19; ChIP-chip, chromatin immunoprecipitation in conjunction with microarray chips; DAC, 5-aza-2′-deoxycytidine; HDAC, histone deacetylase; OSE, ovarian surface epithelium; RT-PCR, reverse transcription–polymerase chain reaction; TGF-β, transforming growth factor-beta; TGFβR, transforming growth factor-beta receptor; TSA, trichostatin A Address all correspondence to: Kenneth P. Nephew, PhD, Medical Sciences, Indiana University School of Medicine, 302 Jordan Hall, 1001 East Third Street, Bloomington, IN 47405-4401. E-mail: [email protected]; or Huey-Jen L. Lin, PhD, Human Cancer Genetics Program, Comprehensive Cancer Center, and Medical Technology Division, School of Allied Medical Professions, College of Medicine, The Ohio State University, Suite 535C, Atwell Hall, 453 W. 10th Avenue, Columbus, OH 43210-1234. E-mail: [email protected] 1This work was supported in part by the National Cancer Institute grants U54 CA113001, R01CA 085389, and 085289; R21 CA110475; Department of Defense Idea Award; American Cancer Society grant (Ohio Division); and by funds from the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and from the Phi Beta Psi Sorority (Brownsburg, Indiana). 2This article refers to supplementary materials, which are designated by Tables W1 and W2 and Figures W1 and W2 and are available online at www.neoplasia.com. Received 1 May 2008; Revised 1 May 2008; Accepted 24 May 2008 Copyright © 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.08540
ASJC Scopus subject areas
- Cancer Research
