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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
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.
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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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