<i>Cic</i> Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

Abstract

Inactivating mutations in the transcriptional repression factor <i>Capicua</i> (<i>CIC</i>) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated <i>Cic</i>-deficient mice and human oligodendroglioma cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. <i>In vitro</i> cultured neural stem cells derived from <i>Cic</i> conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. <i>Cic</i> is known to participate in gene suppression that can be relieved by EGFR signal, but we found that <i>cic</i> also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that <i>Cic</i> loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for <i>Cic</i> in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how <i>CIC</i> mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma. <i>Cancer Res; 77(22); 6097-108. ©2017 AACR</i>.