Aryl hydrocarbon receptor regulates histone deacetylase 8 expression to repress tumor suppressive activity in hepatocellular carcinoma

Abstract

Histone deacetylase 8 (HDAC8), a unique member of class I histone deacetylases, shows remarkable correlation with advanced disease stage and multiple malignant tumors However, little is known about the contribution of HDAC8 to the tumorigenesis of hepatocellular carcinoma (HCC). The present study investigated the expression of HDAC8 regulated by the aryl hydrocarbon receptor (AHR) in HCC cell lines and tissues, and the roles of HDAC8 overexpression in cell proliferation, including potentially underlying mechanisms. We assessed the correlation between the clinic-pathological parameters and the expression of AHR and HDAC8. Further, we analyzed the AHR siRNA transfection and HDAC8 inhibitors to explore the functions of HDAC8 in HCC progression in vitro and in vivo. In a panel of 289 HCC patients, HDAC8 was shown to be highly correlated with AHR expression at both mRNA and protein levels. HCC patients with high AHR expression showed a shorter survival time than that with low AHR expression. We then found that the expression of both AHR and HDAC8 was significantly upregulated in both HCC cell lines and tumor tissues compared to human normal hepatocytes and matched non-tumor tissues. Furthermore, HDAC8 inhibition remarkably inhibited hepatoma cell proliferation and transformation activity via upregulation of RB1 in vitro and in vivo. Our data revealed an important role of the AHR-HDAC8 axis in promoting HCC tumorigenesis, thus identifying HDAC8 as a potential therapeutic target for HCC treatment.

Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine‐specific homeobox expression

“…Here, we provided further evidence of the various effects of the AHR expression level on the prognosis of HCC. The difference in survival outcomes between the medium and high AHR groups appears to be determined, in part, by changes in the expression levels of the tumor suppressor genes p53 and RB and of the proto‐oncogenes , ISX, CCND1 , and E2F1 . Our previous clinical data and tumor cell analysis showed that high AHR expression was associated with low tumor suppressor protein (p53 and RB) expression but higher proto‐oncogene ( ISX, CCND1 , and E2F1 ) expression in vitro and in vivo .…”

“…To assess the potential tumorigenic activity of AHR, we analyzed gene expression patterns in paired samples of tumors from patients in the high and low AHR expression groups via microarray analysis . Expression of the oncogene ISX was elevated in high‐ AHR HCC tumors and was coupled with increases in the downstream genes CCND1 and E2F1 . To explore the potential functional relationship between AHR and ISX , ISX expression levels were evaluated in hepatoma cells treated with AHR ligand.…”

“…The difference in survival outcomes between the medium and high AHR groups appears to be determined, in part, by changes in the expression levels of the tumor suppressor genes p53 and RB and of the proto‐oncogenes , ISX, CCND1 , and E2F1 . Our previous clinical data and tumor cell analysis showed that high AHR expression was associated with low tumor suppressor protein (p53 and RB) expression but higher proto‐oncogene ( ISX, CCND1 , and E2F1 ) expression in vitro and in vivo . Although the detailed mechanisms underlying differential HCC prognostic outcomes remain unclear, AHR overexpression has been shown to inhibit p53 expression and activity in various cell lines and animal models, thereby contributing to tumor progression .…”

“…The chromatin immunoprecipitation (ChIP) assays were performed as described previously . All data are expressed as the mean ± SD of at least three experiments.…”

“…In addition to cellular detoxification, AHR is known to regulate signal transduction pathways involved in cellular proliferation, differentiation, and apoptosis. Disturbances in the cellular functions of AHR have also been associated with the manifestation of various diseases …”