Up-regulation of IRF-3 expression through GATA-1 acetylation by histone deacetylase inhibitor in lung adenocarcinoma A549 cells

Abstract

Interferon regulatory factor 3 (IRF-3) is an important transcription factor for interferon genes. Although its functional activation by viral infection has been widely explicated, the regulatory mechanism of IRF-3 gene expression in cancer cells is poorly understood. In this study, we demonstrated treatment of lung adenocarcinoma A549 cells with trichostatin A (TSA) and valproic acid (VPA), two different classes of histone deacetylase inhibitors, strongly stimulated IRF-3 gene expression. Truncated and mutated IRF-3 promoter indicated that a specific GATA-1 element was responsible for TSA-induced activation of IRF-3 promoter. Chromatin immunoprecipitation and electrophoretic mobility shift assay showed that TSA treatment increased the binding affinity of GATA-1 to IRF-3 promoter. Using immunoprecipitation assay and immunoblotting, we demonstrated that TSA increased the level of acetylated GATA-1 in A549 cells. In summary, our study implied that TSA enhanced IRF-3 gene expression through increased GATA-1 recruitment to IRF-3 promoter and the acetylation level of GATA-1 in lung adenocarcinoma A549 cells.

Sodium Valproate Inhibits Small Cell Lung Cancer Tumor Growth on the Chicken Embryo Chorioallantoic Membrane and Reduces the p53 and EZH2 Expression

“…It significantly inhibits the growth and induces the apoptosis of different glioblastoma cell lines depending on the used doses 43 ; the 8 mmol/L NaVP dose in the U-87 cells tumor on CAM reduced tumor invasion by 90% 18 ; NaVP concentrations of 1 to 3 mmol/L induced cell differentiation and apoptosis of poorly differentiated thyroid cancer cells 43 , 44 ; NaVP inhibited prostate cancer cell migration by upregulating the E-cadherin expression 45 ; and the 5 to 10 mmol/L NaVP concentrations significantly induced the expression of the tumor suppressor gene IRF-3 in cancer cells, inhibiting non-small lung cancer cell growth. 46 Sodium valproate might markedly increase the sensitivity of lung adenocarcinoma cells resistant to erlotinib, thus strengthening NaVP as a potential medicine for resistant cancer therapy. 47…”

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates

“…81,82 Valproic acid is reported to be a class I histone deacetylase (HDAC) inhibitor commonly used to treat mood disorders and epilepsy. Its anticancer effect has been reported in several cancers in recent years, including lung adenocarcinoma, [83][84][85] through modulations of epigenetic patterns via HDAC inhibition and gene expression modification. Furthermore, many of the MR candidates retrieved by our analyses have reported or suggested epigenetic mechanisms of modulation, which further supports the study and search for pharmacological epigenetic controllers in cancer therapy research.…”

Epigenetic Modifications and Potential Treatment Approaches in Lung Cancers

“…Although the interferon regulatory factor 3 (IRF-3), an important transcription factor for interferon genes, is often functional in viral infections, the regulation mechanism of IRF-3 expression in cancers has not been fully understood. The concurrent use of histone deacetylase inhibitors and Trichostatin A (TSA) has been shown to increase IRF-3 expression in lung adenocarcinoma A549 cells by altering GATA-1 acetylation, and targeting IRF-3 is therefore thought to be a novel therapeutic approach [32].…”

“…Some homologues identified in mammals include XIAP, cIAP1, cIAP2, NAIP, Bruce, Survivin and IAP. Most of these block cell death by directly binding to and inhibiting caspase-3, caspase-7 and caspase-9[32].Various diseases may arise in the event of any defect within the regulation of apoptosis. Among these, cancer is a condition characterised by little or no apoptosis.…”