MEDB-89. Elucidation of the Oncogenic role of Nuclear Factor I/B (NFIB) in group 3 medulloblastoma

Amongst the 4 subgroups of medulloblastoma (MB), tumors falling into group 3 are the most aggressive and associated with increased incidence of aberrations on chromosome 17p, c-Myc amplification, metastases at diagnosis, and rapid tumor relapse. Thus, patients with group 3 tumors suffer the worst prognosis with a 5-year survival rate of <50%. We have prior identified a novel tumor-suppressive microRNA, miR-212, silenced on chromosome 17p and its deregulated oncoprotein target, Nuclear Factor I/B (NFIB). Here, we sought to identify the role of NFIB in group 3 MB pathophysiology. NFIB is a transcription factor that regulates chromosomal gene accessibility and expression of pro-metastatic genes in various cancers. Transcriptomic interrogation of group 3 tumors revealed deregulated expression of NFIB. Kaplan-Meier survival analysis confirmed poorer survival in NFIB high-expressing patients. Using inducible silencing of NFIB in a classic group 3 MB cell line, HDMB03, we observed downregulation of key driver genes (49 genes, Log2 fold change < -0.5, p < 0.001) associated with group 3 MB pathogenesis by RNA sequencing. NFIB expression knockdown (NFIB(KD)) further reduced tumor cell growth and aggressiveness, as evidenced by reduced proliferation, colony formation, migration, and invasion. NFIB(KD) also affected group 3 MB stemness, with attenuation of medullospheres and a reduction in stem cell markers (Nanog, Oct4, Sox2, CD133). Moreover, NFIB(KD) destabilized c-Myc phosphorylation at serine-62, resulting in reduced total c-Myc levels and subsequent cellular apoptosis. Concurrently, NFIB(KD) decreased the expression of upstream activators of c-Myc such as p-Akt and p-Erk. Taken together, these results validate the oncogenic role of NFIB in group 3 medulloblastomas and provide a potential new therapeutic target.