Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer

Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predic...

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Autores principales:	Robson Francisco Carvalho, Luisa Matos do Canto, Sarah Santiloni Cury, Torben Frøstrup Hansen, Lars Henrik Jensen, Silvia Regina Rogatto
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	rectal cancer drug repositioning reverse expression of signature genes gene expression features drug reversal potency scoring Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2f8dc78127b245109a3a9f766d7f5edc
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spelling	oai:doaj.org-article:2f8dc78127b245109a3a9f766d7f5edc2021-11-11T15:33:42ZDrug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer10.3390/cancers132154922072-6694https://doaj.org/article/2f8dc78127b245109a3a9f766d7f5edc2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5492https://doaj.org/toc/2072-6694Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (<i>TOP2A)</i> gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the <i>TOP2A</i> has the highest efficacy in reducing cellular proliferation. Finally, we observed significant <i>TOP2A</i> copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate <i>TOP2A</i> status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.Robson Francisco CarvalhoLuisa Matos do CantoSarah Santiloni CuryTorben Frøstrup HansenLars Henrik JensenSilvia Regina RogattoMDPI AGarticlerectal cancerdrug repositioningreverse expression of signature genesgene expression featuresdrug reversal potency scoringNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5492, p 5492 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	rectal cancer drug repositioning reverse expression of signature genes gene expression features drug reversal potency scoring Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	rectal cancer drug repositioning reverse expression of signature genes gene expression features drug reversal potency scoring Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Robson Francisco Carvalho Luisa Matos do Canto Sarah Santiloni Cury Torben Frøstrup Hansen Lars Henrik Jensen Silvia Regina Rogatto Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
description	Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (<i>TOP2A)</i> gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the <i>TOP2A</i> has the highest efficacy in reducing cellular proliferation. Finally, we observed significant <i>TOP2A</i> copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate <i>TOP2A</i> status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.
format	article
author	Robson Francisco Carvalho Luisa Matos do Canto Sarah Santiloni Cury Torben Frøstrup Hansen Lars Henrik Jensen Silvia Regina Rogatto
author_facet	Robson Francisco Carvalho Luisa Matos do Canto Sarah Santiloni Cury Torben Frøstrup Hansen Lars Henrik Jensen Silvia Regina Rogatto
author_sort	Robson Francisco Carvalho
title	Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
title_short	Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
title_full	Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
title_fullStr	Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
title_full_unstemmed	Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer
title_sort	drug repositioning based on the reversal of gene expression signatures identifies <i>top2a</i> as a therapeutic target for rectal cancer
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2f8dc78127b245109a3a9f766d7f5edc
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Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies <i>TOP2A</i> as a Therapeutic Target for Rectal Cancer

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