Upregulation of Stat1-HDAC4 confers resistance to etoposide through enhanced multidrug resistance 1 expression in human A549 lung cancer cells

Abstract

Despite efforts to develop efficient chemotherapeutic drug strategies to treat cancer, acquired drug resistance is a commonly encountered problem. In the present study, to investigate this phenomenon, human A549 lung cancer cells resistant to the topoisomerase inhibitor etoposide (A549RT‑eto) were used and compared with A549 parental cells. A549RT‑eto cells demonstrated increased resistance to etoposide‑induced apoptosis when compared with A549 parental cells. Notably, A549RT‑eto cells were observed to exhibit greater levels of histone deacetylase 4 (HDAC4), phospho‑Stat1 and P‑glycoprotein [P‑gp; encoded by the multidrug resistance 1 (MDR1) gene], compared with A549 cells. To address whether HDAC4 protein is involved in etoposide resistance in A549 cells, A549RT‑eto cells were treated with trichostatin A (TSA; an HDAC inhibitor) during etoposide treatment. The combined treatment was demonstrated to enhance etoposide‑induced apoptosis and reduce expression levels of HDAC4, P‑gp and phospho‑Stat1. In addition, the suppression of Stat1 with siRNA enhanced etoposide‑induced apoptosis and reduced the expression levels of HDAC4 and P‑gp, suggesting that Stat1 is essential in the regulation of resistance to etoposide, and in the upregulation of P‑gp. Notably, TSA treatment reduced P‑gp transcript levels but Stat1 siRNA treatment did not, suggesting that P‑gp is regulated by HDAC at the transcriptional level and by Stat1 at the post‑transcriptional level. These results suggest that the upregulation of Stat1 and HDAC4 determines etoposide resistance through P‑gp expression in human A549 lung cancer cells.

HDAC2 overexpression is a poor prognostic factor of breast cancer patients with increased multidrug resistance-associated protein expression who received anthracyclines therapy

“…Chao et al (35) revealed that the mRNA expression of MRP in ovarian cancer cell was reduced after HDACs inhibitors treatments. Kaewpiboon et al (36) found that the level of PgP in human lung cancer cells resistant to etoposide was increased, and could be reversed by HDACs inhibitors. Therefore, in vitro studies have not demonstrated consistent results about the influence of HDAC inhibitor treatments on expression of tumor drug-resistance-related proteins.…”

MiR‐520b restrains cell growth by targeting HDAC4 in lung cancer

“…Gastric cancer progression can be enhanced by HDAC4 via p21 inhibition . STAT1/HDAC4 augmentation makes human A549 lung cells resistant to etoposide via increased MDR1 . High levels of HDAC4 are found and contribute to oncogenesis in liver cancer .…”

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

“…This has been shown as HDAC overexpression leads to more effective detoxification due to the HDAC2 and 4 dependent expression of the efflux pump p-glycoprotein. Consequently, colorectal and lung cancer cells resist doxorubicin and etoposide, respectively, which could be reversed upon HDACi application (17,49). HDACi furthermore influence detoxification by decreasing the levels of glutathione, thereby sensitising squamous cell carcinoma cells to cisplatin (50), a known target of detoxification by glutathione (51).…”