Vorinostat, SAHA, represses telomerase activity via epigenetic regulation of telomerase reverse transcriptase in non-small cell lung cancer cells

Abstract

Vorinostat (suberoylanilide hydroxamic acid), a class of histone deacetylase inhibitors, represents an emerging class of anticancer agents currently progressing in clinical trials. It causes cell growth inhibition, differentiation, and apoptosis of many tumor types in vitro and in vivo. Recently, it was reported that hTERT is one of the targets for cancer therapy in cancer cells. Telomerase repeat amplification protocol assay was used to analyze the expression of hTERT after vorinostat treatment in the A549 lung cancer cells. Vorinostat inhibited telomerase activity by reducing the expression of human telomerase reverse transcriptase (hTERT) in A549 human lung cancer cells. The epigenetic regulation mechanism is responsible for the repression of hTERT by vorinostat, analyzed through the methylation-specific PCR and bisulfite sequencing of the hTERT promoter. Vorinostat induced the demethylation of site-specific CpGs on the promoter region of hTERT, which was caused by the down-regulation of DNA methyltransferases. DNA methyltransferases (DNMT1 and DNMT3b) were also decreased in vorinostat-treated A549 cancer cells. Furthermore, chromatin immunoprecipitation analysis of the hTERT promoter revealed that vorinostat decreased the level of inactive chromatin markers dimethyl-H3K9, and the declined binding of DNMT1 and DNMT3b were associated. The novel insights showed that vorinostat down-regulated telomerase via epigenetic alteration in lung cancer to vorinostat-mediated cancer-specific therapies.

Cancer Epigenetics: Mechanisms and Crosstalk of a HDAC Inhibitor, Vorinostat

“…Vorinostat has currently been proven to restore altered methylation patterns as therapeutic means in chronic myeloid leukemia and non-small cell lung cancer (NSCLC) [3,48]. Among the studies conducted on various cancers, the studies on lung cancer demonstrate one of the most effective usages of vorinostat as an anticancer agent controlling the methylation pattern.…”

“…Among the studies conducted on various cancers, the studies on lung cancer demonstrate one of the most effective usages of vorinostat as an anticancer agent controlling the methylation pattern. In the study conducted on NSCLC cells, for example, vorinostat was proven to successfully repress the telomerase activity via epigenetic regulation of methylation patterns [48]. The human telomerase reverse transcriptase (hTERT) is known to provide major contributions to the immortality of cancer cells by protecting the lengths of the ends of chromosomes [48].…”

Epigenetics in lung cancer diagnosis and therapy

“…It has been shown to cause cell growth inhibition, differentiation, and apoptosis of different tumor types both in vitro and in vivo [118]. Vorinostat also reduced the expression of human telomerase reverse transcriptase (hTERT) in A549 cells by inducing DNA demethylation at the first exon of hTERT [119].…”

Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma

“…Evidence suggests that vorinostat can promote the demethylation of site-specific CpGs on the promoter region of hTERT by downregulating DNMTs such as DNMT1 and DNMT3b. 83 In recent years, Shukla and colleagues 84 show that cucurbitacin B (CuB) can dampen the activity of two epigenetic players, such as DNMTs and HDACs, precisely at a very low dose of 60 nmol/L in H1299 cells. Their study suggests that downstream effects of blocking of DNMTs and HDACs in H1299 cells may lead to downregulation of cancer-supporting genes including telomerase and could serve as an option for anticancer drugs.…”