Abstract 3205: Histone tyrosine phosphorylation determines glioblastoma cell survival

Abstract

Abstract Histone modification is crucial for cell signaling pathways and regulates predominantly chromatin functions related with DNA damage response (DDR) that lead cancer cells to survive upon different therapies. Receptor tyrosine kinases (RTKs) have been extensively studied in cancer progression and DDR and, recently, several reports described the role of RTKs in histone tyrosine modification. We have been focusing on the role of the receptor tyrosine kinase, TIE2, in gliomas. Our study identified the expression of TIE2 in human surgical glioma specimens in relation to malignancy, specifically in brain tumor stem cells. We have revealed that the unexpected membrane-to-nuclear trafficking of TIE2 is related with radioresistance of brain tumor stem cells, functioning as a genotoxic stress sensor to activate DNA repair machinery. Interestingly, TIE2 binds, upon IR stress, to DNA/protein complexes and phosphorylates several core histones. The tandem mass spectrum of H4 and H2B demonstrates that TIE2 directly phosphorylates not previously described H4pY51 and H2BY40 respectively, which reinvigorates TIE2's role in histone code modification. We screened for pY-readers using a SH2 domain array and found that H4pY51 and H2pY40 modifications are read by the proto-oncogenes ABL1 and CRK, respectively. Our data also showed that TIE2/H4pY54/ABL1 complex binds to DNA repair proteins, activating an NHEJ DNA repair mechanism. We summarize that upon IR stress TIE2 localizes to the nucleus where it is involved in key cellular functions by directly phosphorylating core histones, and recruiting SH2 domain proteins to the DNA damage sites, complexing to the DNA repair machinery, which in turns results in radioresistance. Our data highlight the role of epigenetics in modulating the DNA damage response of glioma radiation therapy and open new avenues to find novel targetable pathways for treatment of patients with glioblastomas. Citation Format: Mohammad Belayat Hossain, Rehnuma Shifat, Debora K. Kim, Yiesel Rivera-Molina, Francisco Puerta Martinez, Hong Jiang, Teresa Nguyen, David G. Johnson, Mark T. Bedford, Mien-Chie Hung, Erik P. Sulman, Frederick Lang, Raymond Sawaya, Juan Fueyo, Candelaria Gomez-Manzano. Histone tyrosine phosphorylation determines glioblastoma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3205.