Musashi1 Contribution to Glioblastoma Development via Regulation of a Network of DNA Replication, Cell Cycle and Division Genes

• Published in: Cancers Vol. 13; no. 7; p. 1494
• Main Authors: Baroni, Mirella, Yi, Caihong, Choudhary, Saket, Lei, Xiufen, Kosti, Adam, Grieshober, Denise, Velasco, Mitzli, Qiao, Mei, Burns, Suzanne S, Araujo, Patricia R, DeLambre, Talia, Son, Mi Young, Plateroti, Michelina, Ferreira, Marco A R, Hasty, Paul, Penalva, Luiz O F
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.03.2021; MDPI
• Subjects: Brain cancer; Cancer; Cell cycle; Cell division; Cell self-renewal; Cellular Biology; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA methylation; Drug dosages; Gene expression; Gene mapping; Gene regulation; Genomes; Genomic analysis; Glioblastoma; Life Sciences; Medulloblastoma; Musashi protein; Nervous system; Neurobiology; Neurons and Cognition; Replication; RNA-binding protein; Stem cells; Subcellular Processes; Transcription factors; Tumorigenesis; Tumors; DNA replication; glioblastoma; cell cycle; cell division; E2F2; Musashi1; E2F8
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13071494

RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in their levels are often observed in tumors with numerous oncogenic RBPs identified in recent years. Musashi1 (Msi1) is an RBP and stem cell gene that controls the balance between self-renewal and differentiation. High Msi1 levels have been observed in multiple tumors including glioblastoma and are often associated with poor patient outcomes and tumor growth. A comprehensive genomic analysis identified a network of cell cycle/division and DNA replication genes and established these processes as Msi1's core regulatory functions in glioblastoma. Msi1 controls this gene network via two mechanisms: direct interaction and indirect regulation mediated by the transcription factors E2F2 and E2F8. Moreover, glioblastoma lines with Msi1 knockout (KO) displayed increased sensitivity to cell cycle and DNA replication inhibitors. Our results suggest that a drug combination strategy (Msi1 + cell cycle/DNA replication inhibitors) could be a viable route to treat glioblastoma.