Abstract 4909: Olig2 phosphorylation by CDK2 implicated in glioma proliferation.

Abstract

Abstract Oligodendrocyte transcription factor 2 (Olig2) is an important proneural transcription factor that regulates early development of the central nervous system and formation of glioma. Although recent studies established the role of developmentally regulated Olig2 phosphorylation in promoting the proliferation of both normal and malignant neural stem/progenitor cells, the molecular mechanisms by which Olig2 phosphorylation is regulated and functions as a pro-proliferative factor are not completely understood. Here we identified Olig2 as a critical phosphorylation target for cyclin-dependent kinase 2 (CDK2). CDK2 stabilizes and activates Olig2, thereby regulating G1-to-S phase progression by repressing the expression of Cyclin-dependent kinase inhibitor p27kip1. After phosphorylation by CDK2, Olig2 exerts pro-proliferative effects that are reflected in normal neural/glioma stem cells and in murine xenograft models of glioma. Olig2 phosphorylation regulates its binding to E-box sequence in p27 gene promoter and represses p27 expression. We show that constitutive p27 expression antagonizes CDK2-mediated Olig2 phosphorylation and attenuates cell proliferation both in in-vitro and in-vivo glioma models. Expression analysis of TCGA GBM samples also showed that high Olig2 expression is always accompanied with high CDK2 expression in the proneural, classical, and neural subclasses, which could provide a convincing evidence to use a CDK2 inhibitor to treat Olig2-high gliomas. Treatment with CDK2 inhibitor preferentially suppresses proliferation of Olig2-high glioma cells. Thus, we conclude that a CDK2 inhibitor could be of great therapeutic value in patients with Olig2-high glioma and Olig2 might be used as a biological marker for CDK2 inhibitors in the future studies. Citation Format: Jun Fu, Dimpy Koul, Siyuan Zheng, Vivek Singh, Jun Yao, Yanhua Zheng, Zhimin Lu, Erik P. Sulman, Frederick F. Lang, Alfred W.K Yung. Olig2 phosphorylation by CDK2 implicated in glioma proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4909. doi:10.1158/1538-7445.AM2013-4909