Histone deacetylase inhibitors regulate P-gp expression in colorectal cancer via transcriptional activation and mRNA stabilization

Abstract

Histone deacetylase inhibitors (HDACIs) are emerging as a novel class of anti-tumor drugs. But the effect of HDACIs in tumors treatment has been disappointing, which mainly due to the acquisition of resistance to HDACIs. However, the underlying mechanisms have not been clearly understood. In this study, it was found that HDACIs SAHA and TSA increased P-gp expression in CRC cells, which has been well known to contribute to drug resistant. The mechanisms underlying these effects were investigated. We showed that HDACIs enhanced transcriptional activity of P-gp protein encoding gene ABCB1. HDACIs treatment also increased the protein and mRNA expression of STAT3, but not PXR, CAR, Foxo3a or β-catenin, which are known to be involved in ABCB transcription regulation. Interestingly, knockdown of STAT3 significantly attenuated HDACIs-induced P-gp up-regulation in colorectal cancer cells, suggesting that STAT3 plays a crucial role in HDACIs-up-regulated P-gp. Furthermore, this study revealed for the first time that HDACIs enhanced the stability of ABCB1 at post-transcriptional level. Taken together, these results proved that HDACIs induced P-gp expression by two distinct ways, transcriptional activation and mRNA stabilization. Our results suggested that more attention should be paid to the cancer treatment using HDACIs since they will induce multidrug resistance in cancer cells.

Effects of histone deacetylase inhibitors on ATP‑binding cassette transporters in lung cancer A549 and colorectal cancer HCT116 cells

“…For instance, the HDAC inhibitors SAHA, TSA and phenylbutyrate were reported to increase ABCB1 expression in acute myeloid leukemia (29). Our previous study revealed that SAHA, TSA and sodium butyrate induced ABCB1 expression by transcriptional activation of STAT3, and stabilized ABCB1 mRNA in lung and colorectal cancer (22,23). Consistently, the present study also demonstrated that SAHA and TSA significantly increase ABCB1 mRNA and protein expression in A549 and HCT116 cells.…”

“…Our previous study and other previous research have demonstrated that treatment of cancer cells with HDAC inhibitors increases the expression of ABCB1, which results in the development of an MDR phenotype (22,23). However, the effects of HDAC inhibitors on other MDR-associated ABC transporters have not previously been reported.…”

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

“…These studies have since been repeated using different HDAC inhibitors. SAHA and TSA upregulated P-gp expression in HCT116 colorectal cancer cells within 25 h of exposure [114]. P-gp expression was upregulated at two different steps, translational initiation and mRNA stabilization [115], and HDAC inhibitors increase P-gp expression in both stages [115].…”

Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer

“…In this study, we assessed the mechanism through which ivermectin regulates YAP1 function for the first time and demonstrated that ivermectin decreased YAP1 mRNA expression, resulting in reduced nuclear expression of YAP1 protein in GC cells (Figure 5B ). Ivermectin-induced YAP1 mRNA downregulation was assumed to occur through transcriptional inactivation or mRNA destabilization [ 19 ]. Further experiments are required to clarify this mechanism.…”