HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression

Our plain-English summary of HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression, by P.F. Cartron, C. Blanquart, E. Hervouet, et al (Molecular Oncology, 2013).

The study

• Authors: P.F. Cartron, C. Blanquart, E. Hervouet, M. Gregoire, F.M. Vallette
• Journal: Molecular Oncology
• Published: 2013;7(3):452-63
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies. Despite the identification of the epigenetical silencing of the NY-ESO1 gene in a large variety of tumors, the molecular mechanism involved in this phenomenon is not fully elucidated. In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes. Thus, our data illustrate the orchestration of a sequential epigenetic mechanism including the histone deacetylation and methylation, and the DNA methylation processes.

Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

In plain English

This laboratory study looked at how a gene called NY-ESO1 is switched off in cancer cells. Some tumors make the NY-ESO1 protein, and the immune system can recognize it. The authors used cultured human glioma cells (the U251 cell line) and mesothelioma tumor cells (M96). Mesenchymal stem cells, which express the gene, served as the comparison. The study did not examine asbestos exposure. Part of the gene's control (promoter) region was methylated, a chemical tag linked to gene silencing, in U251 and M96 cells but not in the stem cells. Three protein groups were found on this region. In timed experiments on U251 cells they arrived in order: HDAC1-mSin3A-NCOR1, then Dnmt3b-HDAC1-Egr1, then Dnmt1-PCNA-UHRF1-G9a. Blocking any one of four of these proteins alone did not switch the gene on. In U251 cells, the drug 5-aza-2-deoxycytidine switched it on and valproic acid alone did not. Combined, the two worked best across the cells tested. A NY-ESO1-specific T-cell clone responded to U251 and M96 cells only after 5-aza treatment. The authors concluded that their data describe the proteins regulating this gene.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell culture) experiment on human cancer cells, using DNA methylation tests, chromatin immunoprecipitation, gene knockdown with siRNA, drug treatments and a T-cell activation test
• Who was studied: Cultured human cells: glioma cell lines U251 and LN18, primary-cultured glioblastoma (GBM) tumor cells G1 and G2, the mesothelial cell line Met5A, and primary-cultured mesothelioma tumor cells M13, M34 and M96. Mesenchymal stem cells (MSC) were used as a positive control. Most mechanistic work used U251 and M96 cells.
• Exposure: No asbestos exposure was studied. Experimental treatments were siRNA knockdown of Dnmt1, Dnmt3b, HDAC1 or G9a, and the epigenetic drugs valproic acid (VPA) and/or 5-aza-2-deoxycytidine (5aza), each given for 7 consecutive days.
• Main results:
  • The studied promoter region of NY-ESO1 was methylated in U251 (glioma) and M96 (mesothelioma) cells and unmethylated in mesenchymal stem cells.
  • Among the histone deacetylases tested, only HDAC1 was recruited to this region in U251 and M96 cells. The histone methyltransferase G9a was recruited, but SUV39H1 and SetDB1 were not.
  • Knocking down Dnmt1, Dnmt3b, HDAC1 or G9a individually did not induce NY-ESO1 mRNA expression (all p greater than 0.05).
  • In timed experiments on synchronized U251 cells, the HDAC1-mSin3A-NCOR1 complex was recruited first, then the Dnmt3b-HDAC1-Egr1 complex, and finally the Dnmt1-PCNA-UHRF1-G9a complex.
  • In U251 cells, valproic acid alone did not induce NY-ESO1 mRNA expression.
  • In U251 cells, 5aza treatment induced NY-ESO1 mRNA expression.
  • Across the panel of glioma and mesothelioma cells, the combination of VPA and 5aza was the most effective treatment for inducing NY-ESO1 mRNA expression.
  • A NY-ESO1-specific CD8+ T-cell clone produced interferon-gamma only in response to 5aza-treated U251 and M96 cells. It did not respond to untreated tumor cells.
• The authors' conclusion: The authors concluded that their data describe the proteins involved in the epigenetic regulation of the NY-ESO1 gene. They also wrote that the results open a promising antitumor role for VPA/5aza treatment in mesothelioma and glioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma.

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