A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance

• Published in: Blood 2013-04, Vol.121 (17), p.3459-3468
• Main Authors: Santoro, Fabio, Botrugno, Oronza A., Dal Zuffo, Roberto, Pallavicini, Isabella, Matthews, Geoffrey M., Cluse, Leonie, Barozzi, Iros, Senese, Silvia, Fornasari, Lorenzo, Moretti, Simona, Altucci, Lucia, Pelicci, Pier Giuseppe, Chiocca, Susanna, Johnstone, Ricky W., Minucci, Saverio
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Female; Flow Cytometry; Genomic Instability; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - antagonists & inhibitors; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Leukemia, Promyelocytic, Acute - etiology; Leukemia, Promyelocytic, Acute - mortality; Leukemia, Promyelocytic, Acute - prevention & control; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Survival Rate; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - physiology; Valproic Acid - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-10-461988

Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML-RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR–expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdac1 has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells. •Hdac1 and, to a lesser extent, Hdac2 behave as oncosuppressors during tumor initiation, but they work as oncogenes in tumor maintenance.•Class I HDAC inhibitors (VPA) accelerate tumorigenesis in murine models of leukemia, which suggests caution in their clinical use.