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

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...

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Bibliographic Details
Published in:Blood Vol. 121; no. 11; p. 2038
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 14.03.2013
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
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:1528-0020, 1528-0020
Online Access:Get more information
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Summary: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.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2012-08-450916