Abstract 4519: ATM/ATR-SerRS pathway dominates hypoxic angiogenesis in tumor

Hypoxia-induced angiogenesis is a critical response in multicellular organisms to maintain oxygen homeostasis. It is also an important mechanism to support tumor progression. Hypoxia activates hypoxia-inducible factor (HIF) and HIF-independent pathways to transcriptionally induce the expression of pro-angiogenic genes. However, our knowledge on transcriptional repressors of angiogenesis and how they are regulated during hypoxia are limited. Here we report that seryl-tRNA synthetase (SerRS), a newly identified transcriptional repressor of vascular endothelial growth factor (VEGFA), is a major inhibitor of angiogenesis that is inactivated during hypoxia1-4. Inactivation of SerRS is achieved through its phosphorylation at serine 101 and serine 241 by ataxia telangiectasia mutated (ATM) and the related kinase ATR. Knockdown of HIF is not sufficient to completely block hypoxia-induced VEGFA expression in human cells unless a phosphorylation-deficient form of SerRS (SerRSS101A/S241A) is simultaneously expressed to escape ATM/ATR inactivation. Consistently, in mice, SerRSS101A/S241A can bypass hypoxia response despite HIF activation to strongly inhibit angiogenesis in a matrigel assay and a xenograft model of human breast cancer. These findings reveal ATM/ATR-SerRS pathway as a key negative regulator of angiogenesis related to hypoxia and a new target for cancer therapy. References 1. Fukui, H., Hanaoka, R., and Kawahara, A. (2009). Noncanonical activity of seryl-tRNA synthetase is involved in vascular development. Circ Res 104, 1253-1259. 2. Herzog, W., Muller, K., Huisken, J., and Stainier, D. Y. (2009). Genetic evidence for a noncanonical function of seryl-tRNA synthetase in vascular development. Circ Res 104, 1260-1266. 3. Shi, Y., Xu, X., Zhang, Q., Fu, G., Mo, Z., Wang, G. S., Kishi, S., and Yang, X. L. (2014). tRNA synthetase counteracts c-Myc to develop functional vasculature. Elife 3, e02349. 4. Xu, X., Shi, Y., Zhang, H. M., Swindell, E. C., Marshall, A. G., Guo, M., Kishi, S., and Yang, X. L. (2012). Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun 3, 681. Citation Format: Yi Shi, Ze Liu, Xiang-Lei Yang. ATM/ATR-SerRS pathway dominates hypoxic angiogenesis in tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4519. doi:10.1158/1538-7445.AM2017-4519