RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer.
Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promoter-targeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications.
Authors' Affiliations: Institute of Oncology Research; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and Molecular Oncology Unit, CIEMAT, Madrid, Spain.
Gianluca
G
Civenni
Anastasia
A
Malek
Domenico
D
Albino
Ramon
R
Garcia-Escudero
Sara
S
Napoli
Stefano
S
Di Marco
Sandra
S
Pinton
Manuela
M
Sarti
Giuseppina M
GM
Carbone
Carlo V
CV
Catapano
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering