Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

Abstract

Epigenetic deregulation is involved in acute myeloid leukemia (AML) pathogenesis and epigenetic targeting drugs are in clinical trial. Since the first results with histone-deacetylase inhibitors in AML are controversial, novel single and combined treatments need to be explored. It is tempting to combine chromatin-targeting drugs. SUV39H1, the main methyl-transferase for lysine 9 tri-methylation on histone H3, interacts with oncogenes involved in AML and acts as a transcriptional repressor for hematopoietic differentiation and immortalization. We report here that pharmacological inhibition of SUV39H1 by chaetocin induces apoptosis in leukemia cell lines in vitro and primary AML cells ex vivo, and that it interferes with leukemia growth in vivo. Chaetocin treatment upregulates reactive oxygen species (ROS) production as well as the transcription of death-receptor-related genes, in a ROS-dependent manner, leading to death receptor-dependent apoptosis. In addition to its direct inhibition by chaetocin, SUV39H1 is indirectly modulated by chaetocin-induced ROS. Accordingly, chaetocin potentiates other anti-AML drugs, in a ROS-dependent manner. The decryption of a dual mechanism of action against AML involving both direct and indirect SUV39H1 modulation represents an innovative read-out for the anticancer activity of chaetocin and for its synergy with other anti-AML drugs, suggesting new therapeutic combination strategies in AML.

Chaetocin-induced ROS-mediated apoptosis involves ATM–YAP1 axis and JNK-dependent inhibition of glucose metabolism

“…6 As gliomas are refractory to current treatment strategies, we investigated whether Chaetocin could affect glioma cell proliferation. Treatment with Chaetocin induced glioma cell death in a dose- (Figure 1a) and time- (Figure 1b) dependent manner.…”

“…6 As we have reported that elevated ROS level induces glioma cell apoptosis, 2 we determined ROS levels in Chaetocin-treated cells with reduced thioredoxin reductase activity. A significant 4–6-fold increase in ROS production was observed in A172, T98G and U87MG glioma cells upon Chaetocin treatment indicated by increased DCFDA and DHE fluorescence intensity (Figure 1d).…”

“…5 Inhibition of SUV39H1, an H3K9me3-specific methyltransferase, by Chaetocin prevents leukemia cell growth in a ROS-dependent manner. 6 As ROS-inducing agents effectively kill cancer cells through elevation of intracellular ROS, 1 we investigated whether Chaetocin could also affect survival and growth of glioma cells through oxidative stress induction.…”

Nucleophilic Mechanism of ROS/RNS Signaling in Cancer Epigenetic Modifications

“…It has been shown that the treatment of human hepatoma cells with curcumin (Cur) (dietary pigment derived from Curcuma longa) led to a significant ROS-dependent HAT-catalyzed decrease in histone acetylation [25]. The HAT inhibitor chaetocin suppressed methyltransferase SUV39H1through lysine 9 trimethylation on histone H3 and induced apoptosis in leukemia cells by a ROS-dependent mechanism [26]. All these conflicting data are presented in Figure 3.…”

“…Chaetocin ROS SUV39H1 (HAT) histone H3Me 3 trimethlation Leukemia cell apoptosis [26] Overexpression of Sirt1 suppressed ROS formation produced by the adaptor protein p66Shc and inhibited high glucose-induced p66Shc upregulation in human umbilical vein endothelial cells. It was suggested that Sirt1suppressed the acetylation of histone H3 bound to p66Shc promoter region [33].…”