Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer1-4. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.
Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway / A. Insinga, S. Monestiroli, S. Ronzoni, V. Gelmetti, F. Marchesi, A. Viale, L. Altucci, C. Nervi, S. Minucci, P.G. Pelicci. - In: NATURE MEDICINE. - ISSN 1078-8956. - 11:1(2005 Jan), pp. 71-76.
Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway
S. Minucci;P.G. Pelicci
2005
Abstract
Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer1-4. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.Pubblicazioni consigliate
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