Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function

• Published in: Blood Vol. 121; no. 11; pp. 2038 - 2050
• Main Authors: Heideman, Marinus R., Wilting, Roel H., Yanover, Eva, Velds, Arno, de Jong, Johann, Kerkhoven, Ron M., Jacobs, Heinz, Wessels, Lodewyk F., Dannenberg, Jan-Hermen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-03-2013; American Society of Hematology
• Subjects: Animals; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Cells, Cultured; Epistasis, Genetic - physiology; Gene Dosage - genetics; Gene Dosage - physiology; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Genes - physiology; Genes, Tumor Suppressor - physiology; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone Deacetylase 1 - physiology; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Histone Deacetylase 2 - physiology; Lymphoid Neoplasia; Lymphoma - genetics; Lymphoma - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins c-myc - physiology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-450916

Histone deacetylases (HDACs) are epigenetic erasers of lysine-acetyl marks. Inhibition of HDACs using small molecule inhibitors (HDACi) is a potential strategy in the treatment of various diseases and is approved for treating hematological malignancies. Harnessing the therapeutic potential of HDACi requires knowledge of HDAC-function in vivo. Here, we generated a thymocyte-specific gradient of HDAC-activity using compound conditional knockout mice for Hdac1 and Hdac2. Unexpectedly, gradual loss of HDAC-activity engendered a dosage-dependent accumulation of immature thymocytes and correlated with the incidence and latency of monoclonal lymphoblastic thymic lymphomas. Strikingly, complete ablation of Hdac1 and Hdac2 abrogated lymphomagenesis due to a block in early thymic development. Genomic, biochemical and functional analyses of pre-leukemic thymocytes and tumors revealed a critical role for Hdac1/Hdac2-governed HDAC-activity in regulating a p53-dependent barrier to constrain Myc-overexpressing thymocytes from progressing into lymphomas by regulating Myc-collaborating genes. One Myc-collaborating and p53-suppressing gene, Jdp2, was derepressed in an Hdac1/2-dependent manner and critical for the survival of Jdp2-overexpressing lymphoma cells. Although reduced HDAC-activity facilitates oncogenic transformation in normal cells, resulting tumor cells remain highly dependent on HDAC-activity, indicating that a critical level of Hdac1 and Hdac2 governed HDAC-activity is required for tumor maintenance.
•Hdac1 and Hdac2 are dosage-dependent tumor suppressors.•Hdac1 and Hdac2 regulate p53-modulating genes as a barrier to prevent Myc-driven tumorigenesis.