Poster abstracts
Poster number 24 submitted by Jae Bucknor
Understanding how ncRNA Impact the NRF2 Antioxidant Response in Lung Cancer
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 elevated levels of NRF2 protein, a transcription factor and master regulator of the cellular antioxidant response pathway. The accumulation of NRF2 results in increased activation of cytoprotective genes, that are responsible for increasing detoxification, efflux, and resistance to oxidative stressors. Thus, elevated NRF2 activity contributes to increased NSCLC therapy resistance and enables cancer progression. Many noncoding RNAs of unknown function are also expressed when NRF2 is activated, and these noncoding RNAs (ncRNAs) could represent novel ways to target the NRF2 pathway therapeutically. Depletion of ncRNAs that support NRF2 activity could sensitize NSCLC to existing therapies. I confirmed the expression of dozens of ncRNAs in multiple NSCLC cell lines with activated NRF2 by RNA sequencing. I hypothesize that NRF2 activated ncRNA may contribute to NSCLC by supporting NRF2 stability, NRF2 transcriptional activity, and or antioxidant activity. I identified several high confidence ncRNA candidates (activated in all or almost all cell lines tested), including previously identified ncRNA LUCAT1 and NMRAL2P and uncharacterized ncRNAs LOC102723825 and LOC105374811. I aim to understand the mechanism of NRF2 pathway activity by these ncRNA. To do this, I will characterize RNA secondary structures and protein-interaction networks through live cell chemical probing of NSCLC lines (SHAPE-MaP and RNP-MaP). After identifying these motifs, I will identify the critical RNA motifs that interact with 1) KEAP1 to support NRF2 stabilization, 2) DNA to support NRF2 transcriptional activity, or 3) NRF2 effector proteins to support antioxidant activity. Then, I will evaluate these ncRNA’s functional contribution to NRF2 signaling and on NSCLC proliferation and migration. The ultimate goal of this work is to evaluate NRF2 activated ncRNA’s potential as NSCLC therapeutic target.
References:
1. Siegel et al., CA Cancer J Clin. 2021.
2. GBD 2019 Cancer Risk Factors Collaborators, Lancet. 2022.
3. Jason Hoffman, Healthline. 2022.
4. Campbell et al., Nat Genet. 2016.
5. He et al., Carcinogenesis. 2020.
6. Abdalkader et al., Front Neurosci. 2018.
7. Wu et al., Toxicol Sci. 2011.
8. Venugopal et al., Proc Natl Acad Sci U S A. 1996.
9. Kobayashi et al., Nat Commun. 2016.
10. Singh et al., PLoS Med. 2006.
11. Siegfried et al., Nat Methods. 2014.
12. Weidmann et al., Nat Biotechnol. 2021.
13. Dodel et al., Nat Methods. 2024.
Keywords: ncRNA, lung cancer, antioxidant