- Inactivate the two-faced HDAC-brake: Cell cycle regulation and tumor suppression by histone deacetylases HDAC1 and HDAC2
M.M.S. van Lohuizen
- Award date
- 13 November 2013
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Histone deacetylases (HDACs) counterbalance acetylation of histone and nonhistone proteins, which regulate gene expression among other critical biological processes. Epigenetic modifications are reversible, and therefore, inhibitors of epigenetic regulators, like HDAC inhibitors (HDACi) are developed to revert aberrant histone modifications in cancer. To improve therapeutic potential of HDACi, it is crucial to understand the role of individual HDACs in cell development. Therefore we investigated the role of Hdac1 and Hdac2 in cell cycle progression, hematopoietic differentiation, and tumor development, using conditional knockout (cKO) alleles in mice.
Hdac1 and Hdac2 are critical for maintaining cell cycle progression, since combined deletion or inactivation of Hdac1 and Hdac2, in primary or oncogenic-transformed mouse fibroblasts, resulted in a senescence-like G1 cell cycle arrest.
In vivo dual inactivation of Hdac1 and Hdac2 in hematopoietic cells resulted in apoptosis of megakaryocytes with concomitant anemia and thrombocytopenia, suggesting that similar toxicities observed in patients treated with HDACi are caused by on-target inhibition.
Unexpectedly, we identified Hdac1 and Hdac2 as tumor suppressors. Systematic combination of Hdac1 and Hdac2 cKO alleles in murine thymi resulted in dosage-dependent tumor development of monoclonal lymphoblastic lymphomas, characterized by Myc-oncogene overexpression and a novel p53-suppressing mechanism.
In human tumors, we identified somatic mutations catalytically inactivating HDAC1. These inactive HDAC1 mutants had a dominant-negative effect on regulating histone acetylation, suggesting a tumor-driving capacity of heterozygous inactivating HDAC1 mutations.
Furthermore, screening for lower HDAC-expression levels and inactivating mutations may serve as diagnostic tools for HDACi sensitivity, since lowered HDAC-activity increased HDACi-mediated tumor cell eradication.
- Research conducted at: Universiteit van Amsterdam
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