ArticleGastroenterology2008
An inactivating mutation in HDAC2 leads to dysregulation of apoptosis mediated by APAF1.
Article in Gastroenterology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 58 citations in OpenAlex.
- Targeting Aromatase and HDACs in Hormone Receptor-Positive Breast Cancer: Molecular Interplay, Endocrine Resistance and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Histone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors.Signal transduction and targeted therapy · 2026Article
- Epigenetic drugs in cancer therapy.Cancer metastasis reviews · 2025Review
- Association of changes in expression ofEpigenetics · 2024Article
- Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA damage response inhibitors.NPJ systems biology and applications · 2024Article
- Pathogenesis and biomarkers of colorectal cancer by epigenetic alteration.Intestinal research · 2024Review
- Cancer epigenetics: from laboratory studies and clinical trials to precision medicine.Cell death discovery · 2024Review
- The epigenetic modifier HDAC2 and the checkpoint kinase ATM determine the responses of microsatellite instable colorectal cancer cells to 5-fluorouracil.Cell biology and toxicology · 2023Article
- Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification.Cell death and differentiation · 2023Article
- Characterizing HDAC Pathway Copy Number Variation in Pan-Cancer.Pathology oncology research : POR · 2022Article
- Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response.Nature communications · 2021Article
- Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer.Metabolites · 2021Review
- Epigenetics of colorectal cancer: biomarker and therapeutic potential.Nature reviews. Gastroenterology & hepatology · 2020Review
- HDAC Inhibitors in Acute Myeloid Leukemia.Cancers · 2019Review
- Identification of key genes and construction of microRNA-mRNA regulatory networks in multiple myeloma by integrated multiple GEO datasets using bioinformatics analysis.International journal of hematology · 2017Article
- Marked for death: targeting epigenetic changes in cancer.Nature reviews. Drug discovery · 2017Review
- HDAC inhibition activates the apoptosome via Apaf1 upregulation in hepatocellular carcinoma.European journal of medical research · 2016Article
- Epigenetic modulators, modifiers and mediators in cancer aetiology and progression.Nature reviews. Genetics · 2016Review
- Driver mutations of cancer epigenomes.Protein & cell · 2014Article
- Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer.Investigational new drugs · 2013Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsHistone deacetylases (HDACs) are important regulators of chromatin involved in silencing tumor suppressor genes. We examined mutation of HDAC2 and examined consequences of HDAC2 loss.
methodsColon cancer cell lines and primary cancers were examined for mutations in HDAC2 by direct sequencing and capillary electrophoresis. Promoter methylation was determined using methylation-specific polymerase chain reaction in primary tumors. Sensitivity to HDAC inhibitors and resistance in vitro used colon cancer cell lines.
resultsHDAC2 mutations in the poly(A) tract in exon 1 result in a frameshift and premature stop codon. These were found in microsatellite instability (MSI) cell lines and 43% of MSI colon cancers, but only 7% of microsatellite stable cancers. Mutation was associated with complete or regional tumor specific loss of HDAC2 protein. Inactivation of HDAC2 was not associated with large-scale changes in promoter region methylation, but rather is a consequence of epigenetic MLH1 inactivation leading to MSI. HDAC2 mutation results in apoptotic resistance to HDAC inhibitors (trichostatin A or suberoylanilide hydroxamic acid), despite induction of global histone acetylation. Differential induction of apoptosis by HDAC inhibitors is mediated by the proapoptotic gene APAF1, as shown by specific APAF1 induction only in cell lines with functional HDAC2, HDAC2 protein localization to the APAF1 promoter by chromatin immunoprecipitation, siRNA knockdown of HDAC2 leading to up-regulation of APAF1, and stable knockdown of APAF1 reducing apoptotic response to HDAC inhibitors.
conclusionsFrequent HDAC2 mutations are found in MSI tumors and HDAC2 plays a major role in mediating apoptotic response to HDAC inhibitors through direct regulation of APAF1.
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