Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

• Published in: Clinical cancer research Vol. 23; no. 9; pp. 2143 - 2153
• Main Authors: Kudinov, Alexander E, Karanicolas, John, Golemis, Erica A, Boumber, Yanis
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.05.2017
• Subjects: Aberration; Biological activity; Cancer; Cell Movement - genetics; Chromatin; Compartments; Drosophila; Drug resistance; Epigenetics; Fruit flies; Gene expression; Gene Expression Regulation, Neoplastic; Glioblastoma; Hematopoietic stem cells; Humans; Leukemia; Lung cancer; Metastases; Molecular Targeted Therapy; mRNA stability; Musashi protein; Myc protein; Neoplasm Invasiveness - genetics; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - pathology; Nerve Tissue Proteins - genetics; NUMB protein; Pancreas; Pancreatic cancer; Progenitor cells; Proteins; PTEN protein; Regulators; Ribonucleic acid; RNA; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-mediated interference; Signaling; Smad3 protein; Stem cells; TOR protein; Transcription factors; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-16-2728

Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) 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 a regulator of progenitor cell identity in , 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, TGFβ/SMAD3, MYC, cMET, and others. On the basis of these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis, and development of more aggressive cancer phenotypes, including drug resistance. Although 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. .