Nuclear Factor I A Promotes Temozolomide Resistance in Glioblastoma via Transcriptional Regulation of Nuclear Factor κB Pathway

Background: Glioma is one of the most common primary brain tumors in human with severe mortality based on its therapy resistance and recurrence. Many molecular pathways and regulation factors have been proved to be required for GBM growth and therapy resistance, however, the underlying molecular mechanisms still remains unclear. Methods: Nuclear factor I-A (NFIA) was identified as a key candidate kinase encoding gene in chemoresistance regulation by using kinome-wide bioinformatic analysis. Afterwards, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, western blotting and in vivo xenograft models followed by temozolomide (TMZ) resistant U87 cell induction. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of AURKB in glioma patients. At last, lentiviral silencing of NFIA was used to explore the potential downstream targets for NFIA in acquired TMZ resistance in GBM.. Results: We identified NFIA was the most correlated gene for TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated to adverse outcomes of glioma patients especially in GBM patients. Moreover, NFIA was functionally required for TMZ resistance of U87 cells while suppression of NFIA via lentivirus infection reduced cell proliferation, tumorigenesis as well as resistance to TMZ in GBM cells. Lastly, NFIA promoted acquired TMZ resistance in GBM via transcription activity thus regulated the expression of nuclear factor κB (NF-kB). Conclusions: Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to the acquired TMZ resistance in GBM, indicating that NFIA-NF-κB axis could be a new therapeutic target for TMZ resistant GBM.