Shi Bin, Xu Fang-Fang, Xiang Cai-Ping, Jia Ru, Yan Chun-Hong, Ma Se-Qing, Wang Ning, Wang An-Jiao, Fan Ping
Department of Anorectal Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230000, P.R. China.
Department of Anorectal Surgery, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230000, P.R. China.
Oncol Lett. 2020 Nov;20(5):148. doi: 10.3892/ol.2020.12011. Epub 2020 Aug 24.
Histone deacetylase (HDAC) inhibitors and DNA alkylators are effective components of combination chemotherapy. The aim of the present study was to investigate the possible mechanism of their synergism by detecting the effect of HDAC inhibitors on the expression levels of drug transporters that export DNA alkylators. It was demonstrated that the HDAC inhibitor sodium butyrate (NaB) induced the differential expression of multidrug resistant ATP-binding cassette (ABC) transporters in lung cancer and colorectal cancer cells. Specifically, NaB increased the mRNA expression levels of and , and protein expression levels of multidrug resistance-1 (MDR1), multidrug resistance-associated protein 7 (MRP7) and MRP9. Moreover, NaB decreased the expression levels of and mRNAs, as well as those of MRP1, MRP2 and MRP3 proteins. The molecular mechanism underlying this process was subsequently investigated. NaB decreased the expression of HDAC4, but not HDAC1, HDAC2 or HDAC3. In addition, NaB promoted histone H3 acetylation and methylation at lysine 9, as well as MDR1 acetylation, suggesting that acetylation and methylation may be involved in NaB-mediated ABC transporter expression. Thus, the present results indicated that the synergism of the HDAC inhibitors with the DNA alkylating agents may due to the inhibitory effect of MRPs by HDAC inhibitors. The findings also suggested the possibility of antagonistic effects following the combined treatment of HDAC inhibitors with MDR1 ligands.
组蛋白脱乙酰酶（HDAC）抑制剂和DNA烷化剂是联合化疗的有效成分。本研究的目的是通过检测HDAC抑制剂对输出DNA烷化剂的药物转运蛋白表达水平的影响，来探究它们协同作用的可能机制。结果表明，HDAC抑制剂丁酸钠（NaB）可诱导肺癌和结肠癌细胞中多药耐药ATP结合盒（ABC）转运蛋白的差异表达。具体而言，NaB增加了 和 的mRNA表达水平，以及多药耐药蛋白1（MDR1）、多药耐药相关蛋白7（MRP7）和MRP9的蛋白表达水平。此外，NaB降低了 和 的mRNA表达水平，以及MRP1、MRP2和MRP3蛋白的表达水平。随后对这一过程的分子机制进行了研究。NaB降低了HDAC4的表达，但未降低HDAC1、HDAC2或HDAC3的表达。此外，NaB促进了赖氨酸9处组蛋白H3的乙酰化和甲基化，以及MDR1的乙酰化，表明乙酰化和甲基化可能参与了NaB介导的ABC转运蛋白表达。因此，本研究结果表明，HDAC抑制剂与DNA烷化剂的协同作用可能是由于HDAC抑制剂对MRP的抑制作用。研究结果还提示了HDAC抑制剂与MDR1配体联合治疗后产生拮抗作用的可能性。
