Abstract
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.
Highlights
Prostate cancer is the most common epithelial cancer and the third leading cause of cancer-related death in men in the western countries [1, 2]
We show that RNA interference (RNAi)-based transcriptional silencing of Myc is an effective strategy to block maintenance and propagation of prostate cancer stem-like cells (CSC) in cell cultures and tumor xenografts
This study demonstrates the efficacy of the RNAi-based strategy for targeting regulatory noncoding promoter-associated RNA (paRNA) and modulating transcription of genes involved in critical oncogenic pathways
Summary
Prostate cancer is the most common epithelial cancer and the third leading cause of cancer-related death in men in the western countries [1, 2]. Considerable progress has been made in the last decade to understand the disease at the molecular and genetic level [3, 4]. There has been limited improvement in the treatment of advanced, castration-resistant prostate cancer There is increasing evidence that most human cancers, including prostate cancer, are driven by a rare population of cancer cells that display stem cell–like properties, defined as cancer stem-like cells (CSC) or tumor-initiating cells [6]. CSCs within primary tumors are likely the main cause of metastasis and disease recurrence [6, 7]. CSCs contribute to treatment failures by virtue of their intrinsic resistance to standard treatment, including chemo- and radiotherapy
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