Poster abstracts
Poster number 123 submitted by Jae Bucknor
Probing the Mechanism of NRF2 Co-Activated lncRNA NMRAL2P in NSCLC
Jae A. Bucknor (Cellular and Molecular Biology, University of Michigan), Brittany M. Bowman (Biological Chemistry, University of Michigan), Chase A. Weidmann (Biological Chemistry, University of Michigan)
Abstract:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. More than 25% of cases of NSCLC display aberrantly elevated levels of NRF2 protein, a transcription factor that regulates an antioxidant response. NRF2 protein activates expression of cytoprotective genes responsible for increasing detoxification, efflux, and resistance to oxidative stressors. Thus, NRF2 pathway overactivity contributes to cancer progression by enabling cells to resist oxidative stress and increased NSCLC therapy resistance through the accelerated elimination of drug molecules. Many long non-coding RNAs (lncRNAs) are also expressed with NRF2 activation, and their role in the antioxidant response is not well understood. Based on RNA-sequencing, I find that the shared set of annotated genes that are significantly upregulated upon NRF2 activation by mutation or chemical activation, and in a variety of NSCLC cell lines are majority lncRNAs. Among these lncRNAs, I identified lncRNA NMRAL2P which has been suggested to bind NRF2 and antioxidant target gene promoters to facilitate transcriptional activation of NRF2 targets in colorectal and head and neck cancers. To test this in NSCLC, I will first characterize NMRAL2P RNA secondary structure and protein-interaction networks through live cell chemical probing and mutational profiling of NRF2 active NSCLC cell lines. Then, I will identify NMRAL2P-bound proteins and antioxidant target gene promoters through mass spectrometry and chromatin immunoprecipitation. I will also evaluate NMRAL2P’s impact on NSCLC proliferation, migration, and invasion in the presence of chemotherapeutic agents. This project will characterize how lncRNA NMRAL2P governs NRF2 pathway activity, which may be targeted to treat NSCLC or sensitize NSCLC to existing cancer therapies. LncRNA are exciting new candidates for cancer therapeutics: their large size presents significant, unique surface area not traditionally targeted therapeutically.
Keywords: lncRNA, NRF2, Lung Cancer