Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance

Cancer stem cells (CSCs) have been identified in several solid malignancies and are now emerging as a plausible target for drug discovery. Beside the questionable existence of CSCs specific markers, the expression of CD133 was reported to be responsible for conferring CSC aggressiveness. Here, we id...

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Main Authors:	Zizza, Pasquale, Cingolani, Chiara, Artuso, Simona, Salvati, Erica, Rizzo, Angela, D'Angelo, Carmen, Porru, Manuela, Pagano, Bruno, Amato, Jussara, Randazzo, Antonio, Novellino, Ettore, Stoppacciaro, Antonella, Gilson, Eric, Stassi, Giorgio, Leonetti, Carlo, Biroccio, Annamaria
Format:	Online
Language:	English
Published:	Oxford University Press 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770210/

id	pubmed-4770210
recordtype	oai_dc
spelling	pubmed-47702102016-02-29 Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance Zizza, Pasquale Cingolani, Chiara Artuso, Simona Salvati, Erica Rizzo, Angela D'Angelo, Carmen Porru, Manuela Pagano, Bruno Amato, Jussara Randazzo, Antonio Novellino, Ettore Stoppacciaro, Antonella Gilson, Eric Stassi, Giorgio Leonetti, Carlo Biroccio, Annamaria Gene regulation, Chromatin and Epigenetics Cancer stem cells (CSCs) have been identified in several solid malignancies and are now emerging as a plausible target for drug discovery. Beside the questionable existence of CSCs specific markers, the expression of CD133 was reported to be responsible for conferring CSC aggressiveness. Here, we identified two G-rich sequences localized within the introns 3 and 7 of the CD133 gene able to form G-quadruplex (G4) structures, bound and stabilized by small molecules. We further showed that treatment of patient-derived colon CSCs with G4-interacting agents triggers alternative splicing that dramatically impairs the expression of CD133. Interestingly, this is strongly associated with a loss of CSC properties, including self-renewing, motility, tumor initiation and metastases dissemination. Notably, the effects of G4 stabilization on some of these CSC properties are uncoupled from DNA damage response and are fully recapitulated by the selective interference of the CD133 expression. Oxford University Press 2016-02-29 2015-10-27 /pmc/articles/PMC4770210/ /pubmed/26511095 http://dx.doi.org/10.1093/nar/gkv1122 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Zizza, Pasquale Cingolani, Chiara Artuso, Simona Salvati, Erica Rizzo, Angela D'Angelo, Carmen Porru, Manuela Pagano, Bruno Amato, Jussara Randazzo, Antonio Novellino, Ettore Stoppacciaro, Antonella Gilson, Eric Stassi, Giorgio Leonetti, Carlo Biroccio, Annamaria
spellingShingle	Zizza, Pasquale Cingolani, Chiara Artuso, Simona Salvati, Erica Rizzo, Angela D'Angelo, Carmen Porru, Manuela Pagano, Bruno Amato, Jussara Randazzo, Antonio Novellino, Ettore Stoppacciaro, Antonella Gilson, Eric Stassi, Giorgio Leonetti, Carlo Biroccio, Annamaria Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance
author_facet	Zizza, Pasquale Cingolani, Chiara Artuso, Simona Salvati, Erica Rizzo, Angela D'Angelo, Carmen Porru, Manuela Pagano, Bruno Amato, Jussara Randazzo, Antonio Novellino, Ettore Stoppacciaro, Antonella Gilson, Eric Stassi, Giorgio Leonetti, Carlo Biroccio, Annamaria
author_sort	Zizza, Pasquale
title	Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance
title_short	Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance
title_full	Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance
title_fullStr	Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance
title_full_unstemmed	Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance
title_sort	intragenic g-quadruplex structure formed in the human cd133 and its biological and translational relevance
description	Cancer stem cells (CSCs) have been identified in several solid malignancies and are now emerging as a plausible target for drug discovery. Beside the questionable existence of CSCs specific markers, the expression of CD133 was reported to be responsible for conferring CSC aggressiveness. Here, we identified two G-rich sequences localized within the introns 3 and 7 of the CD133 gene able to form G-quadruplex (G4) structures, bound and stabilized by small molecules. We further showed that treatment of patient-derived colon CSCs with G4-interacting agents triggers alternative splicing that dramatically impairs the expression of CD133. Interestingly, this is strongly associated with a loss of CSC properties, including self-renewing, motility, tumor initiation and metastases dissemination. Notably, the effects of G4 stabilization on some of these CSC properties are uncoupled from DNA damage response and are fully recapitulated by the selective interference of the CD133 expression.
publisher	Oxford University Press
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770210/
_version_	1613544393459892224

Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance

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