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Musashi RNA-binding proteins as cancer drivers and novel therapeutic targets
Clin Cancer Res. 2017 May 01;23(9) :2143-2153
PMID: 28143872    PMCID: PMC5413399    URL: https://www.ncbi.nlm.nih.gov/pubmed/28143872
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Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. While much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act post-transcriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBPs) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as regulators of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers, glioblastoma, and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGF-beta/SMAD3, MYC, cMET, and others. Based on these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance. While RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target.
Kudinov, Alexander E Karanicolas, John Golemis, Erica A Boumber, Yanis R21 CA191425/CA/NCI NIH HHS/United States Journal Article United States Clin Cancer Res. 2017 Jan 31. pii: clincanres.2728.2016. doi: 10.1158/1078-0432.CCR-16-2728.