Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator for mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the serine/threonine kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. The MELK-dependent activation of FOXM1 results in an increase of mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1 (Polo-like kinase 1). Using neural progenitor cells (NPCs) derived from mouse brains, we found that transgene expression of FOXM1 enhances, while its siRNA-mediated gene silencing diminishes clonal neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases from NPCs, pre-tumorigenic progenitors, and GSCs. As expected, sensitivity of GSCs to pharmacological inhibition of MELK-mediated FOXM1 signaling via the thiazole antibiotic Siomycin A is substantially higher than NPCs. In addition, treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cell culture, and addition of Siomycin A to Temozolomide treatment to mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with the kinase domain of MELK regulates mitotic key genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM.

Citation Format: Kaushal Joshi, Ichiro Nakano. MELK-dependent phosphorylation of FOXM1 is essential for mitotic progression of glioma stem cells. [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 4912. doi:10.1158/1538-7445.AM2013-4912