Abstract 2481: Loss of FUBP1 impairs terminal neuronal differentiation and predisposes neural progenitors for transformation

Abstract

Abstract Loss of terminal differentiation capacity through genetic mutations is a selected genetic event in tumorigenesis. 1p19q co-deletion associated recurrent mutations of far upstream element-binding protein 1 (FUBP1) have been reported from genomic analysis of low- grade oligodendroglioma. It is frequently overexpressed in many human cancers and strongly correlated with disease progression. However, left unanswered is how FUBP1 serves uniquely as a tumor suppressor in the central nervous system. Here we show that expression of FUBP1 is dynamically regulated during neurogenesis, marking specific stages of neuronal differentiation. Loss of FUBP1 in neural stem/progenitor cells (NPC) increased the number of cells fail to terminally differentiate. Knockdown of FUBP1 further blocks differentiation and promotes tumorigenesis collaboratively with the expression of neomorphic isocitrate dehydrorgenase 1 mutant IDH1R132H. Mechanistically FUBP1 is necessary for mini exon 8a splicing of neurospecific isoform of histone demethylase LSD1 (nLSD1). It binds to intron 8 of LSD1 together with a neuron-specific splicing complex containing NOVA1 and 2 and works synergistically with SRRM4 for the inclusion of mini exon 8a. The expression level of nLSD1 is decreased upon loss of FUBP1 in neural progenitors, impairing the terminal neuronal differentiation and maturation. Reinforcing nLSD1 expression in FUBP1-downregulated NPC restores terminal differentiation, establishing nLSD1 as an obligatory effector of FUBP1-dependent neuronal differentiation. Together, these findings establish a direct role for FUBP1 in neuronal differentiation and also uncover the mechanism for its tumor suppressor function in the nervous system. Citation Format: Inah Hwang, Dongqing Cao, Do-Yeon Kim, Tuo Zhang, Jian Hu, Yu Yao, Jihye Paik. Loss of FUBP1 impairs terminal neuronal differentiation and predisposes neural progenitors for transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2481.