title: Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function.
abstract: 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.
authors: Division of Gene Regulation, Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
authors: Marinus R
authors: MR
authors: Heideman
authors: Roel H
authors: RH
authors: Wilting
authors: Eva
authors: E
authors: Yanover
authors: Arno
authors: A
authors: Velds
authors: Johann
authors: J
authors: de Jong
authors: Ron M
authors: RM
authors: Kerkhoven
authors: Heinz
authors: H
authors: Jacobs
authors: Lodewyk F
authors: LF
authors: Wessels
authors: Jan-Hermen
authors: JH
authors: Dannenberg
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004843:Epistasis, Genetic / Q000502:physiology; D018628:Gene Dosage / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D005796:Genes / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2