Abstract 4391: Aberrant transcription factor activity of NRF1, NFE2L2, E2F1, RFX1, and MEF2 associated with severity of astrocytoma
Authors: Bhawe Kaumudi , Felty Quentin , Yoo Changwon , Roy Deodutta 
Published: September 2020

Astrocytoma is the most frequently occurring nervous system cancer in humans. Glioblastoma (GBM) is the most severe form of astrocytoma ([WHO] grade IV), and GBM patients rarely live beyond 5 years. Understanding how transcription factor regulatory networks contribute to the severity of astrocytoma will help identify novel therapeutic strategies for GBM. Nuclear Respiratory Factor 1 (NRF1) is a transcription factor (TF) that we have previously demonstrated as being active in cancer and having the ability to participate in crosstalk with other TFs such as the E2Fs and MYC. We have previously demonstrated that NRF1 gene networks are associated with increased NRF1 gene expression and GBM patient survival outcomes. Here, we examined the TF activity landscape that is differentially expressed in GBM compared to non-tumor tissue and in lower grade (I, II, and III) astrocytoma and their role in disease severity. Activities of 247 TFs including NRF1 were examined using patient mRNA expression data from four independent public datasets including the TCGA. The R package ‘limma' with ‘voom' was used to calculate the differential expression of each gene in the microarray and RNA-Seq datasets included in the present study, and then LRPath was employed to determine TF activity. NRF1 transcription factor (TF) activity is upregulated in glioma, correlates with disease aggressiveness, and is associated with cancer hallmarks and key functional pathways known to be dysregulated in cancer. Further analysis of data from all four patient cohorts including TCGA showed that NRF1 TF activity positively correlates with NFE2L2, E2F1, and RFX1, and negatively correlates with MEF2. Differential activity of these TFs is associated with astrocytoma disease severity. Protein-protein interaction networks (PPIN) were then generated for the TF combinations separately for male and female patients. Downstream gene ontology pathway analysis of the TF target genes revealed that DNA repair (GO:0006281), histone modification (GO:0016570), mitotic cell cycle (GO:0000278), and regulation of neurotransmitter level (GO: 0001505) genes regulated by NFE2L2, E2F1, and RFX1 are upregulated corresponding to increased NRF1 activity, while tissue development (GO: 0009888) genes regulated by MEF2 are down-regulated corresponding to increased NRF1 activity. These findings suggest that aberrant transcription factor activity of NRF1, NFE2L2, E2F1, MEF2, and RFX1 may be involved in the pathogenesis and severity of astrocytoma. Further analysis of these TF-regulated gene signatures combined with patient clinical outcomes will help pave the way for next generation targeted therapies and drug combination strategies for GBM patients.

Citation Format: Kaumudi Bhawe, Quentin Felty, Changwon Yoo, Deodutta Roy. Aberrant transcription factor activity of NRF1, NFE2L2, E2F1, RFX1, and MEF2 associated with severity of astrocytoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4391.