Abstract 5838: RNA methylation regulates autophagy via unfolded protein response in cancers

Abstract

Abstract N6-methyladenosine (m6A) RNA methylation is a dynamic, reversible and most abundant epitranscriptomic modification found on mRNA and long-non coding RNAs. M6A is regulated by methyl transferases (writes m6A), demethylases (erases m6A) and read by specific RNA binding proteins known as m6A readers that can modulate the fate of specific transcript. Recent studies have suggested that RNA methylation affects several fundamental cellular and molecular functions including mRNA splicing, stability, export, stem cell fate, circadian rhythms, DNA repair and cell survival. In addition, we and others have shown that RNA methylation plays an important role in tumor growth and progression. Here, we discovered that m6A may regulate tumorigenesis by regulating autophagy in cancer cells. Our results revealed that altering the levels of m6A methylation led to increased levels of LC3, which is a universal marker for autophagy. In addition, autophagy initiation protein ULK1 and other autophagy complex proteins including ATG5, ATG12, ATG16L1, and LAMP1 levels were significantly increased in cells with altered m6A methylation. Importantly, we discovered that change in m6A levels by altering the RNA demethylase protein induced the unfolded protein response (UPR) pathway, which is a known activator of autophagy. To understand the molecular mechanism of autophagy induction, we looked into three branches of UPR pathways and discovered that protein kinase RNA like kinase (PERK) UPR signaling pathway is highly activated in ALKBH5 depleted cancer cells and might regulate autophagy induction and cancer cell survival. In conclusion, our study is the first investigation to show that RNA methylation plays an important role in cancer growth by regulating autophagy via UPR. Citation Format: Panneerdoss Subbarayalu, Pooja Yadav, Manjeet Rao. RNA methylation regulates autophagy via unfolded protein response in cancers [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 5838.