Abstract 1127: Role of NRF1 regulatory gene-networks in glioblastoma
Authors: Bhawe Kaumudi , Das Jayanta , Yoo Changwon , Roy Deodutta 
Published: August 2018

Nuclear Respiratory Factor 1 (NRF1), a transcription factor historically known to regulate several mitochondrial genes, has been recently implicated in human cancers. We have previously demonstrated the importance of NRF1 in estrogen driven breast cancer. The NRF1 motif exhibits some of the strongest pioneer activity (pioneer index indicates an increase in chromatin opening activity during developmental process) in mouse embryonic stem cells. Both neurogenesis and synaptogenesis are controlled by NRF1 regulated genes. There is a strong association of NRF1 with human fetal brain and neural development. To begin our study of the effect of NRF1 on glioblastoma pathogenesis, we examined whether NRF1 contributes to the acquisition of multipotent neural stem/progenitor cell (NSPC) properties in adult human brain cells. We generated NRF1 overexpressing stable human brain cerebral cortex astrocytes. Both 17β-estradiol (E2, 100 pg/ml) and NRF1 overexpression increased the percentage of cells co-expressing SOX2 and Nestin by 8 and 20%, respectively as shown by flow cytometry. Nestin is an intermediate filament protein important for guaranteeing neural stem pluripotent stem cell (NSPC) self-renewal while SOX2 is expressed at the earliest development stage of the brain and functions as a marker of neural development. SOX2 also plays a key role in the maintenance of neural stem cell (NSC) properties, including proliferation/survival, self-renewal, and neurogenesis. Multipotency allows NSPCs to differentiate into the neurons, astrocytes or oligodendrocytes. NRF1-induced SOX2+Nestin+ NSPCs expressed the neuronal marker β-III-tubulin, the neural phenotype, and neurosphere formation. NRF1 induced NSPCs were subjected to FACS analysis after FITC Annexin V and Propidium Iodide staining. Dead cells stained positive for both FITC Annexin V and PI and these cells are lowest in NRF1+ (0.42%) compared to vector control (4%). In summary, overexpression of NRF1 suppresses cellular senescence and increases resistance to apoptosis. Both are major barriers to cell reprogramming that may contribute in the generation of glioblastoma stem cells. To investigate the role of NRF1 gene network in glioblastoma, we used Bayesian network (BN) analysis on TCGA based RNA-seq data of 154 glioblastoma patients samples. NRF1 based gene association networks were significantly different in low overall survival (OS) patients compared with high OS patients. Specifically, TNFRSF10B, HGF, EBF4, and PAX5 showed up consistently as first degree Markov Blanket genes of NRF1 in low OS (&lt;6mo) glioblastoma patients but not in the high OS patients. In conclusion, these data provide evidence in support of the role for NRF1 in glioblastoma. Clarifying these NRF1 driven complex mechanisms can be a guiding force in the development of new treatments to slow or prevent the development of glioblastoma.

Citation Format: Kaumudi Bhawe, Jayanta Das, Changwon Yoo, Deodutta Roy. Role of NRF1 regulatory gene-networks in glioblastoma [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 1127.