{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T17:27:43Z","timestamp":1771262863902,"version":"3.50.1"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005925","name":"Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The role of TGF\u2010\u03b2 signaling in the epigenetic modifications involved in ovarian cancer is not fully understood. This study investigated the relationship between TGF\u2010\u03b2 signaling, epigenetic modifications, and cellular behaviors in ovarian cancer. We found that E\u2010cadherin, a key cell adhesion molecule, underwent epigenetic silencing via promoter DNA hypermethylation in ovarian cancer cell lines and that this was accompanied by the upregulation of vimentin, which is indicative of a mesenchymal and invasive phenotype. DNA\u2010demethylating agents restored E\u2010cadherin expression, which suggests that TGF\u2010\u03b2 signaling mediates this epigenetic silencing. Overexpression of SMAD7, an inhibitory component of TGF\u2010\u03b2 signaling, reversed E\u2010cadherin silencing, which suggests a role of SMAD7 in modulating the epigenetic status. Functionally, SMAD7 overexpression inhibited the migration and invasion in ovarian cancer cells, which suggests its therapeutic potential for suppressing metastasis. Clinically, ovarian cancer patients with high SMAD7 expression had significantly longer disease\u2010free survival. Mechanistically, SMAD7 overexpression decreased the acetylation of H3K9 and the binding of the transcriptional repressor TWIST1 at the E\u2010cadherin promoter, which promoted its demethylation and reactivation. Disruption of TGF\u2010\u03b2 signaling upregulated SMAD4 target genes, which are silenced by epigenetic mechanisms, a finding that suggests broader therapeutic implications. Overall, our results provide insights into the role of TGF\u2010\u03b2\u2010mediated epigenetic regulation in ovarian cancer metastasis and underscore the therapeutic potential of targeting TGF\u2010\u03b2 signaling and its downstream effectors. Further research is needed to elucidate the underlying mechanisms and validate these therapeutic strategies.<\/jats:p>","DOI":"10.1002\/mc.23843","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T14:29:41Z","timestamp":1731594581000},"page":"290-304","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Role of SMAD7 in the Epigenetic Regulation of TGF\u2010\u03b2 Targets in the Metastasis of Ovarian Cancer"],"prefix":"10.1002","volume":"64","author":[{"given":"Lin\u2010Yu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences National Chung Cheng University Min\u2010Hsiung Chia\u2010Yi Taiwan"},{"name":"Department of Obstetrics and Gynecology Shuang Ho Hospital, Taipei Medical University New Taipei City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu\u2010Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences National Chung Cheng University Min\u2010Hsiung Chia\u2010Yi Taiwan"},{"name":"Department of Chinese Medicine, Dalin Tzuchi Hospital The Buddhist Tzuchi Medical Foundation Dalin Township Chiayi Taiwan"},{"name":"School of Post\u2010Baccalaureate Chinese Medicine, Tzu Chi University Hualien Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian\u2010Liang","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences National Chung Cheng University Min\u2010Hsiung Chia\u2010Yi Taiwan"},{"name":"Department of Research and Development Instrument Center, National Defense Medical Center Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han\u2010Lin","family":"Chou","sequence":"additional","affiliation":[{"name":"Graduate Institute of Toxicology, College of Medicine, National Taiwan University Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia\u2010Chou","family":"Yeh","sequence":"additional","affiliation":[{"name":"School of Post\u2010Baccalaureate Chinese Medicine, Tzu Chi University Hualien Taiwan"},{"name":"Department of Chinese Medicine Sanyi Tzuchi Chinese Medicine Hospital, The Buddhist Tzuchi Medical Foundation Miaoli Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien\u2010Chih","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Kaohsiung Medical University Kaohsiung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung\u2010Cheng","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Shuang Ho Hospital, Taipei Medical University New Taipei City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0314-2437","authenticated-orcid":false,"given":"Michael W. 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