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Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance
Over 21,000 women are diagnosed with ovarian cancer (OC) in the United States each year and over half that number succumb to this disease annually, often due to recurrent disease. A deeper understanding of the molecular events associated with recurrent disease is needed to identify potential targets...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019902/ https://www.ncbi.nlm.nih.gov/pubmed/33828978 http://dx.doi.org/10.3389/fonc.2021.620873 |
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author | Visco, Zachary R. Sfakianos, Gregory Grenier, Carole Boudreau, Marie-Helene Simpson, Sabrina Rodriguez, Isabel Whitaker, Regina Yao, Derek Y. Berchuck, Andrew Murphy, Susan K. Huang, Zhiqing |
author_facet | Visco, Zachary R. Sfakianos, Gregory Grenier, Carole Boudreau, Marie-Helene Simpson, Sabrina Rodriguez, Isabel Whitaker, Regina Yao, Derek Y. Berchuck, Andrew Murphy, Susan K. Huang, Zhiqing |
author_sort | Visco, Zachary R. |
collection | PubMed |
description | Over 21,000 women are diagnosed with ovarian cancer (OC) in the United States each year and over half that number succumb to this disease annually, often due to recurrent disease. A deeper understanding of the molecular events associated with recurrent disease is needed to identify potential targets. Using genome-scale DNA methylation and gene expression data for 16 matched primary-recurrent advanced stage serous epithelial OCs, we discovered that Claudin-1 (CLDN1), a tight junction protein, shows a stronger correlation between expression and methylation in recurrent versus primary OC at multiple CpG sites (R= –0.47 to −0.64 versus R= -0.32 to −0.57, respectively). An independent dataset showed that this correlation is stronger in tumors from short-term (<3y) survivors than in tumors from long-term (>7y) survivors (R= −0.41 to −0.46 versus R= 0.06 to −0.19, respectively). The presence of this inverse correlation in short-term survivors and recurrent tumors suggests an important role for this relationship and potential predictive value for disease prognosis. CLDN1 expression increased following pharmacologic inhibition of DNA methyltransferase activity (p< 0.001), thus validating the role of methylation in CLDN1 gene inhibition. CLDN1 knockdown enhanced chemosensitivity and suppressed cell proliferation, migration, and wound healing (p< 0.05). Stable CLDN1 knockdown in vivo resulted in reduced xenograft tumor growth but did not reach significance. Our results indicate that the relationship between CLDN1 methylation and expression plays an important role in OC aggressiveness and recurrence. |
format | Online Article Text |
id | pubmed-8019902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80199022021-04-06 Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance Visco, Zachary R. Sfakianos, Gregory Grenier, Carole Boudreau, Marie-Helene Simpson, Sabrina Rodriguez, Isabel Whitaker, Regina Yao, Derek Y. Berchuck, Andrew Murphy, Susan K. Huang, Zhiqing Front Oncol Oncology Over 21,000 women are diagnosed with ovarian cancer (OC) in the United States each year and over half that number succumb to this disease annually, often due to recurrent disease. A deeper understanding of the molecular events associated with recurrent disease is needed to identify potential targets. Using genome-scale DNA methylation and gene expression data for 16 matched primary-recurrent advanced stage serous epithelial OCs, we discovered that Claudin-1 (CLDN1), a tight junction protein, shows a stronger correlation between expression and methylation in recurrent versus primary OC at multiple CpG sites (R= –0.47 to −0.64 versus R= -0.32 to −0.57, respectively). An independent dataset showed that this correlation is stronger in tumors from short-term (<3y) survivors than in tumors from long-term (>7y) survivors (R= −0.41 to −0.46 versus R= 0.06 to −0.19, respectively). The presence of this inverse correlation in short-term survivors and recurrent tumors suggests an important role for this relationship and potential predictive value for disease prognosis. CLDN1 expression increased following pharmacologic inhibition of DNA methyltransferase activity (p< 0.001), thus validating the role of methylation in CLDN1 gene inhibition. CLDN1 knockdown enhanced chemosensitivity and suppressed cell proliferation, migration, and wound healing (p< 0.05). Stable CLDN1 knockdown in vivo resulted in reduced xenograft tumor growth but did not reach significance. Our results indicate that the relationship between CLDN1 methylation and expression plays an important role in OC aggressiveness and recurrence. Frontiers Media S.A. 2021-03-22 /pmc/articles/PMC8019902/ /pubmed/33828978 http://dx.doi.org/10.3389/fonc.2021.620873 Text en Copyright © 2021 Visco, Sfakianos, Grenier, Boudreau, Simpson, Rodriguez, Whitaker, Yao, Berchuck, Murphy and Huang http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Visco, Zachary R. Sfakianos, Gregory Grenier, Carole Boudreau, Marie-Helene Simpson, Sabrina Rodriguez, Isabel Whitaker, Regina Yao, Derek Y. Berchuck, Andrew Murphy, Susan K. Huang, Zhiqing Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance |
title | Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance |
title_full | Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance |
title_fullStr | Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance |
title_full_unstemmed | Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance |
title_short | Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance |
title_sort | epigenetic regulation of claudin-1 in the development of ovarian cancer recurrence and drug resistance |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019902/ https://www.ncbi.nlm.nih.gov/pubmed/33828978 http://dx.doi.org/10.3389/fonc.2021.620873 |
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