Abstract P1-04-03: Cross-talk between RNA methyltransferase and demethylase regulates breast cancer growth and progression

Abstract

Abstract The importance of RNA methylation in biological processes has just begun to emerge. However, our understanding of the role and mechanism by which RNA methylation may play a role in tumorigenesis is unclear. Here, we report that RNA N6-adenosine methyltransferase protein METTL14 supports breast cancer growth and progression. We show that METTL14 mediates its pro-tumorigenic function by activating the expression of RNA binding protein HuR and consequently inducing the transcriptional stability of key cell cycle-associated genes, TGFβ and its signaling partners as well as HMGA2, VEGF and PDGF that are known to play critical roles in cancer growth and metastasis. Importantly, m6 A RNA methylation levels of METTL14 target genes were significantly lower in breast cancer patients compared to normal matched controls. The decreased RNA methylation level resulting in increased activity of these target genes in breast cancer patients is regulated by a feedback loop between RNA demethylase ALKBH5 and METTL14. Our results reveal that ALKBH5 regulates the expression of METTL14 and HuR, which in turn transcriptionally stabilizes ALKBH5. Furthermore, we demonstrate that like METTL14, ALKBH5 also supports breast cancer growth and progression. Taken together, these findings suggest that a collaboration between RNA methylation and demethylation machinery may set up a threshold of RNA methylation that ensures the stability of genes that play a vital role in normal cell proliferation; and any perturbation of that threshold may lead to uncontrolled expression/activity of those genes resulting in tumor growth and progression. Citation Format: Subbarayalu P, Eedunuri VK, Timilsina S, Rajamanickam S, Viswanadhapalli S, Abdelfattah N, Onyeagucha BC, Cui X, Mohammad TA, Huang TH-M, Huang Y, Chen Y, Rao MK. Cross-talk between RNA methyltransferase and demethylase regulates breast cancer growth and progression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-03.