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

Pasquale Zizza, Chiara Cingolani, Simona Artuso, Erica Salvati, Angela Rizzo, Carmen D'Angelo, Manuela Porru, Bruno Pagano, Jussara Amato, Antonio Randazzo, Ettore Novellino, Antonella Stoppacciaro, Eric Gilson, Giorgio Stassi, Carlo Leonetti, Annamaria Biroccio

Research output: Contribution to journalArticle

Abstract

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. In conclusion, we provided the first proof of the existence of G4 structures within the CD133 gene that can be pharmacologically targeted to impair CSC aggressiveness. This discloses a class of potential antitumoral agents capable of targeting the CSC subpopulation within the tumoral bulk.

Original languageEnglish
Pages (from-to)1579-1590
Number of pages12
JournalNucleic Acids Research
Volume44
Issue number4
DOIs
Publication statusPublished - Feb 29 2016

ASJC Scopus subject areas

  • Genetics

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    Zizza, P., Cingolani, C., Artuso, S., Salvati, E., Rizzo, A., D'Angelo, C., Porru, M., Pagano, B., Amato, J., Randazzo, A., Novellino, E., Stoppacciaro, A., Gilson, E., Stassi, G., Leonetti, C., & Biroccio, A. (2016). Intragenic G-quadruplex structure formed in the human CD133 and its biological and translational relevance. Nucleic Acids Research, 44(4), 1579-1590. https://doi.org/10.1093/nar/gkv1122