Balanced Epigenetic Regulation of MHC Class I Expression in Tumor Cells by the Histone Ubiquitin Modifiers BAP1 and PCGF1.

Autor:	Wijdeven RH; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, the Netherlands.; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam UMC, Amsterdam, the Netherlands., Luk SJ; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Schoufour TAW; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands., van der Zanden SY; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands., Cabezuelo M; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands., Heemskerk MHM; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Neefjes J; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2024 Feb 01; Vol. 212 (3), pp. 446-454.
DOI:	10.4049/jimmunol.2300263
Abstrakt:	MHC class I (MHC-I) molecules are critical for CD8+ T cell responses to viral infections and malignant cells, and tumors can downregulate MHC-I expression to promote immune evasion. In this study, using a genome-wide CRISPR screen on a human melanoma cell line, we identified the polycomb repressive complex 1 (PRC1) subunit PCGF1 and the deubiquitinating enzyme BAP1 as opposite regulators of MHC-I transcription. PCGF1 facilitates deposition of ubiquitin at H2AK119 at the MHC-I promoters to silence MHC-I, whereas BAP1 removes this modification to restore MHC-I expression. PCGF1 is widely expressed in tumors and its depletion increased MHC-I expression in multiple tumor lines, including MHC-Ilow tumors. In cells characterized by poor MHC-I expression, PRC1 and PRC2 act in parallel to impinge low transcription. However, PCGF1 depletion was sufficient to increase MHC-I expression and restore T cell-mediated killing of the tumor cells. Taken together, our data provide an additional layer of regulation of MHC-I expression in tumors: epigenetic silencing by PRC1 subunit PCGF1. (Copyright © 2024 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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