Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers.

Autor: MacFawn I; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States., Wilson H; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States., Selth LA; Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, South Australia, Australia., Leighton I; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States; Washington and Jefferson College, 60 S. Lincoln Street, Washington, PA 15301, United States., Serebriiskii I; Fox Chase Cancer Center, 333 Cottman Ave. Philadelphia, PA 19111, United States., Bleackley RC; Department of Biochemistry, 474 Medical Sciences Building, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada., Elzamzamy O; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States; West Virginia Clinical and Translational Sciences Institute, School of Medicine, West Virginia University PO Box 9102, Morgantown, WV 26506-9102, United States., Farris J; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States., Pifer PM; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States., Richer J; Department of Pathology, University of Colorado Anschutz Medical Campus, 12800 E 19th Ave, 31 Aurora, CO 80045, United States., Frisch SM; West Virginia University Cancer Institute, 1 Medical Center Drive, West Virginia University, Morgantown, WV 26505, United States; Department of Biochemistry, 1 Medical Center Drive, West Virginia University, Morgantown WV, United States. Electronic address: sfrisch@hsc.wvu.edu.
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2019 Jan; Vol. 105, pp. 137-149. Date of Electronic Publication: 2018 Nov 30.
DOI: 10.1016/j.molimm.2018.11.006
Abstrakt: Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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