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

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 etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.

Overexpression of Sp1 transcription factor induces apoptosis

“…Sp1-binding sites are present in the promoters of many proapoptotic genes such as bax, fas, fas-ligand, trail, caspase-8 and caspase-3 (Black et al, 2001). Sp1-dependent expression of Fas-Ligand and TRAIL has been shown to be involved in the induction of apoptosis in different cell types (Kavurma et al, 2001;Nebbioso et al, 2005). In hamster CCL39 fibroblasts, Sp1-induced apoptosis might involve a death receptor-activated pathway as it is inhibited by caspase-8 inhibitor.…”

“…In the same cells, Sp1 transfection induces cell death by a mechanism that involves the repression of the cell cycle inhibitor p21 expression (Kavurma and Khachigian, 2003). Finally, inhibitors of histone deacetylases selectively induce the apoptosis of tumour cells via the induction of tumour-necrosis factor-related apoptosisinducing ligand (TRAIL) expression (Nebbioso et al, 2005). This process is dependent on the acetylation and the recruitment of Sp1 and Sp3 to the trail promoter.…”

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

“…Both the cytokine Trail, which acts via the death-receptor pathway, and agonistic antibodies that bind to its receptors are known to selectively induce apoptosis in various malignant cells, including leukemias. Recently, the upregulation of TRAIL was identified as a molecular basis for the tumor-selective action of HDAC inhibitors in acute myeloid leukemia (Insinga et al, 2005;Nebbioso et al, 2005). Bcl11b in turn has been found to interact with HDAC1 and HDAC2 within the NuRD nucleosome remodeling complex, and its transcriptional repression activity was abrogated by HDAC inhibitors (Cismasiu et al, 2005).…”

Towards novel paradigms for cancer therapy

“…Indeed, it is well established that resistance can be relieved by a poorly understood phenomenon generally referred to as 'sensitization'. A plethora of sensitizing agents, including ionizing radiation, chemotherapeutic drugs, cytokines as well as HDAC, proteosome or phosphatidylinositol-3-kinase (PI3K)/Akt inhibitors can reverse the TRAIL-resistant phenotype (Figure 3) (Altucci et al, 2001(Altucci et al, , 2005Clarke et al, 2004;Insinga et al, 2005;Nebbioso et al, 2005;Newsom-Davis et al, 2009). Furthermore, administration of inhibitors of the canonical nuclear factor-kB pathway, which has been shown to regulate resistance to TRAIL-induced apoptosis, induces sensitization of cancer cells to TRAIL (Ravi et al, 2001).…”