MB-02 * SONIC HEDGEHOG INDUCES YB-1 IN A YAP-DEPENDENT MANNER TO REGULATE Igf2 EXPRESSION AND PROLIFERATION IN CEREBELLAR GRANULE NEURON PROGENITORS AND MEDULLOBLASTOMA CELLS

Abstract

Interactions between the developmentally essential Sonic hedgehog (Shh) and Insulin-like Growth Factor (IGF) pathways play prominent roles in medulloblastoma (MB), the most common malignant pediatric brain tumor. MB patients undergo surgery, chemotherapy, and radiation, a regimen that carries devastating side effects, emphasizing the need for targeted therapies to improve survival and quality of life. Post-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the SHH-associated subgroup of MB, is driven by Shh and IGF in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3 and is required for IGF2 expression in CGNPs. We show that YB-1 is induced by Shh in CGNPs in a YAP-dependent manner and is found in the germinal layer of the developing cerebellum. We observed that YB-1 is up-regulated across human medulloblastoma subclasses and is elevated in a mouse model for the Shh medulloblastoma subclass. Finally, shRNA-mediated knockdown experiments reveal that YB-1 activity is required for CGNP and medulloblastoma cell (MBC) proliferation in primary cultures and organotypic slice cultures. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and medulloblastoma cells and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.