It appears you don't have support to open PDFs in this web browser. To view this file, Open with your PDF reader
Abstract
Downregulation of HLA class I (HLA-I) impairs immune recognition and surveillance in prostate cancer and may underlie the ineffectiveness of checkpoint blockade. However, the molecular mechanisms regulating HLA-I loss in prostate cancer have not been fully explored. Here, we conducted a comprehensive analysis of HLA-I genomic, epigenomic and gene expression alterations in primary and metastatic human prostate cancer. Loss of HLA-I gene expression was associated with repressive chromatin states including DNA methylation, histone H3 tri-methylation at lysine 27, and reduced chromatin accessibility. Pharmacological DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition decreased DNA methylation and increased H3 lysine 27 acetylation and resulted in re-expression of HLA-I on the surface of tumor cells. Re-expression of HLA-I on LNCaP cells by DNMT and HDAC inhibition increased activation of co-cultured prostate specific membrane antigen (PSMA)27-38-specific CD8+ T-cells. HLA-I expression is epigenetically regulated by functionally reversible DNA methylation and chromatin modifications in human prostate cancer. Methylated HLA-I was detected in HLA-Ilow circulating tumor cells (CTCs), which may serve as a minimally invasive biomarker for identifying patients who would benefit from epigenetic targeted therapies.
Loss of HLA-I gene expression in prostate cancer is associated with repressive chromatin states, which can be reversed by pharmacological DNMT and HDAC inhibition leading to increased activation of co-cultured tumor-specific CD8+ T-cells.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details




1 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675)
2 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Medicine, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675)
3 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Biomedical Engineering, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Pathology, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675)
4 University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin, Madison, Department of Urology, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675)
5 Fred Hutchinson Cancer Research Center, Divisions of Human Biology and Clinical Research, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622); University of Washington, Department of Pathology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657); Johns Hopkins School of Medicine, Department of Pathology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311)