Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic aetiology has stimulated the development of “epigenetic” therapies. Inhibitors of HDACs (HDACi’s) show tumor-selective actions, induce proliferation arrest, maturation and apoptosis of cancer cells in vitro and in vivo, and are currently being tested in clinical trials. Intrigued by the tumor-selective action of HDACi’s we investigated the corresponding mechanism(s) of action. We report that HDACi’s activate tumor-selective TRAIL/Apo2L death signaling in acute myeloid leukemia (AML) cells and patients’ blasts. TRAIL promoter activation is due to inhibition of resident HDACs, acetylation and de novo recruitment of SP1/SP3 to an MS275-response element. The inductions of TRAIL, p21 and differentiation are independent HDACi activities with TRAIL expression being critical for the anti-tumor action of MS275 in vivo. HDACi’s induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of FAB status, karyotype and immunophenotype. No apoptosis was seen in normal CD34+ progenitor cells, indicating that TRAIL is the cancer-selective component in the HDACi action spectrum. Our results identify TRAIL as a master mediator of the anti-cancer action of several signal transduction drugs.

Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukaemia cells.

WEISZ, Alessandro
Supervision
;
2005-01-01

Abstract

Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic aetiology has stimulated the development of “epigenetic” therapies. Inhibitors of HDACs (HDACi’s) show tumor-selective actions, induce proliferation arrest, maturation and apoptosis of cancer cells in vitro and in vivo, and are currently being tested in clinical trials. Intrigued by the tumor-selective action of HDACi’s we investigated the corresponding mechanism(s) of action. We report that HDACi’s activate tumor-selective TRAIL/Apo2L death signaling in acute myeloid leukemia (AML) cells and patients’ blasts. TRAIL promoter activation is due to inhibition of resident HDACs, acetylation and de novo recruitment of SP1/SP3 to an MS275-response element. The inductions of TRAIL, p21 and differentiation are independent HDACi activities with TRAIL expression being critical for the anti-tumor action of MS275 in vivo. HDACi’s induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of FAB status, karyotype and immunophenotype. No apoptosis was seen in normal CD34+ progenitor cells, indicating that TRAIL is the cancer-selective component in the HDACi action spectrum. Our results identify TRAIL as a master mediator of the anti-cancer action of several signal transduction drugs.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/3023268
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