Abstract 5854: TIE2-mediated epigenetic marks regulate therapeutic resistance of glioblastoma
Authors: Hossain Mohammad Belayat , Shifat Rehnuma , Li Jingyi , Rivera-Mokina Yisel , Martinez Francisco Puerta , Johnson David G. , Bedford Mark T. , Hung Mien-Chie , Sulman Erik P. , Lang Frederick , Sawaya Raymond , Fueyo Juan , Gomez-Manzano Candelaria 
Published: July 2017

Abstract
Glioblastomas (GBs), the most common subtype of primary brain tumors in adults, are resistant to current strategies of surgery, irradiation and chemotherapy with a median survival that ranges from 9 to 15 months. GBs invariably recur after therapy due to the presence of cells exhibiting a multidrug-resistance phenotype in the core of the tumor. There is an urgent need of developing the new therapeutic strategies for brain tumor treatment including the identification of novel molecular pathways regulating this resistant phenotype. One of the key phenomena of GB is that tyrosine kinase receptors (TKRs) are abnormally regulated and related to poor treatment outcomes. We have previously reported the expression of TIE2 in human surgical glioma specimens in relation to malignancy, and the role of TIE2 in endothelial-glioma adhesion, tumor invasion and multi-drug resistance of gliomas. Recently, we have identified that the unexpected membrane-to-nuclear trafficking of TIE2 is related to radioresistance of brain tumor stem cells. Interestingly, TIE2 binds, upon IR stress, to DNA/protein complexes and directly phosphorylates core histones. Specifically we discovered a new histone H4 mark (H4pY51) that is read by ABL1. TIE2/H4pY54/ABL1 complex binds to DNA repair proteins, such as ATM, DNA-PK, and pChk2, activating a NHEJ DNA repair mechanism. In an effort to find the molecular mechanisms underlying TIE2 nuclear translocation, we identified that TIE2 binds and directly phosphorylates caveolin-1 (CAV1) at Tyr14 residue in vitro and in vivo. Importantly, CAV1-pTyr14 is necessary for the translocation of both TIE2 and CAV1 to the nucleus. We also uncovered new TIE2-mediated epigenetic marks. Thus, TIE2 binds and phosphorylates histone H2B at Tyr37 and this modification enhances the recruitment of DNA repair proteins to the DNA damage site. Our results 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, that are complexing to the DNA repair machinery. Our discovery related to tyrosine modification of core histones might be of high significance to understand the resistance of cancer to DNA-damage inducers, which eventually might result in the design of TIE2-targeting combinational therapies for patients with GBs.
Citation Format: Mohammad Belayat Hossain, Rehnuma Shifat, Jingyi Li, Yisel Rivera-Mokina, Francisco Puerta Martinez, David G. Johnson, Mark T. Bedford, Mien-Chie Hung, Erik P. Sulman, Frederick Lang, Raymond Sawaya, Juan Fueyo, Candelaria Gomez-Manzano. TIE2-mediated epigenetic marks regulate therapeutic resistance of glioblastoma [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 5854. doi:10.1158/1538-7445.AM2017-5854