HDAC8 Prevents Anthrax Lethal Toxin-induced Cell Cycle Arrest through Silencing PTEN in Human Monocytic THP-1 Cells

Abstract

Anthrax lethal toxin (LeTx) is a cytotoxic virulence factor that causes cell cycle arrest and cell death in various cell types. However, susceptibility to the cytotoxic effects varies depending on cell types. In proliferating monocytes, LeTx has only transient cytotoxic effects due to activation of the phosphoinositide 3-kinase (PI3K)-AKT-mediated adaptive responses. To date, the mechanism of LeTx in activating PI3K-AKT signaling axis is unknown. This study shows that the histone deacetylase 8 (HDAC8) is involved in activating PI3K-AKT signaling axis through down-regulating the phosphatase and tensin homolog 1 (PTEN) in human monocytic THP-1 cells. The HDAC8-specific activator TM-2-51 and inhibitor PCI-34051 enhanced and prevented, respectively, AKT activation and cell cycle progression in LeTx-treated cells. Furthermore, HDAC8 induced tri-methylation of histone H3 lysine 27 (H3K27me3), which is known to suppress PTEN expression, through at least in part down-regulating the H3K27me3 eraser Jumonji Domain Containing (JMJD) 3. Importantly, the JMJD3-specific inhibitor GSK-J4 induced AKT activation and protected cell cycle arrest in LeTx-treated cells, regardless the presence of HDAC8 activity. Collectively, this study for the first time demonstrated that HDAC8 activity determines susceptibility to cell cycle arrest induced by LeTx, through regulating the PI3K-PTEN-AKT signaling axis.

Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts

“…Although the decrease in EZH2 expression in DU-145-luc treated xenografts (Figure 3) could explain in part the loss of H3K27me3 and perhaps there is a link between JMJD3 demethylase and PTEN that could explain these results. Two previous studies in monocytic cells and renal fibrosis have made comparable observations that support this hypothesis (49,50). We noted an effect of JMJD3 inhibition on PTEN expression with a slight decrease, but there was no impact on AKT expression between control and treated mice (Figure 3).…”

JMJD3 in the regulation of human diseases

“…GSK-J4 reduced type 1 diabetes incidence by protecting insulin-producing cells and human islets from cytokine-induced apoptosis and increasing expression of insulin gene and glucose-stimulated insulin secretion (Backe et al 2018). GSK-J4 also induced AKT activation and cell cycle arrest in human THP-1 cells treated with LeTx (Ha et al 2017). Treatment with GSK-J4 in human large B-cell lymphoma cell lines predominantly resulted in down rage of B-cell receptor signaling and BCL6 and introduced apoptosis of large B-cell lymphoma cells (Mathur et al 2017).…”

Synergy of GSK-J4 With Doxorubicin in KRAS-Mutant Anaplastic Thyroid Cancer

“…Several studies have reported that a combination of two or more drugs may benefit patients with anaplastic disease (Saini et al, 2018;Cao et al, 2019;Chintakuntlawar et al, 2019;Schurch et al, 2019). For example, combination sorafenib with quinacrine (Ha et al, 2017) and a combination of the BH3 mimic drug ABT-737 and doxorubicin (Ntziachristos et al, 2014) induced ATC cell apoptosis. Yong Sang Lee et al tested primary cells cultured from ATC patients and found that different combinations of HNHA (a histone deacetylase), lenvatinib (a fibroblast growth factor receptor inhibitor), and sorafenib (a tyrosine kinase inhibitor) were more effective than single drugs (Hjelmeland et al, 2017).…”