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

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

Risultato della ricerca: Articlepeer review

18 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)1579-1590
Numero di pagine12
RivistaNucleic Acids Research
Volume44
Stato di pubblicazionePublished - 2016

All Science Journal Classification (ASJC) codes

  • Genetics

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