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 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.
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Pasquale
P
Zizza
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Chiara
C
Cingolani
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Simona
S
Artuso
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Erica
E
Salvati
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Angela
A
Rizzo
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Carmen
C
D'Angelo
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.
Manuela
M
Porru
Department of Pharmacy, University of Naples 'Federico II', via D. Montesano 49, I-80131 Napoli, Italy.
Bruno
B
Pagano
Department of Pharmacy, University of Naples 'Federico II', via D. Montesano 49, I-80131 Napoli, Italy.
Jussara
J
Amato
Department of Pharmacy, University of Naples 'Federico II', via D. Montesano 49, I-80131 Napoli, Italy.
Antonio
A
Randazzo
Department of Pharmacy, University of Naples 'Federico II', via D. Montesano 49, I-80131 Napoli, Italy.
Ettore
E
Novellino
Dipartimento di Medicina Clinica e Molecolare, Università 'La Sapienza', piazzale Aldo Moro 5, 00185 Rome, Italy.
Antonella
A
Stoppacciaro
Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS UMR7284/INSERM U1081, University of Nice, 06107 Nice, France.
Eric
E
Gilson
Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, 06202 Nice cedex 3, France.
Giorgio
G
Stassi
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy leonetti@ifo.it.
Carlo
C
Leonetti
Area of Translational Research, Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy biroccio@ifo.it.
Annamaria
A
Biroccio
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D054856:G-Quadruplexes; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000235:genetics*; D014176:Protein Biosynthesis
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides