College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea.
Carcinogenesis. 2018 Jan 12;39(1):72-83. doi: 10.1093/carcin/bgx121.
HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452-induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax and decreased Bcl-xL. Moreover, A452 shifted cells away from antiapoptotic (AKT and ERK) pathways and toward proapoptotic (p38) pathways. A452 triggered DNA damage via increased γH2AX and activation of the checkpoint kinase Chk2. A452 induced the suppression of cell migration and invasion. Interestingly, A452 upregulated the expression of PD-L1, which regulates the PD-1 inhibitory pathway in T cells. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215. Therefore, therapeutically targeting HDAC6 may represent a novel strategy for cancer treatment irrespective of the p53 mutation status.
HDAC6 选择性抑制剂是新型表观遗传抗癌药物。然而，其确切的作用机制尚未完全了解。我们研究了新型强效和选择性 HDAC6 抑制剂 A452 与当前临床测试的 HDAC6 抑制剂 ACY-1215 相比的抗癌机制。我们证明 A452 有效抑制各种癌细胞类型的细胞生长和活力，而与 p53 状态无关。A452 诱导的细胞凋亡表现为活化的 caspase 3 和 PARP、增加的 Bak 和 Bax 以及减少的 Bcl-xL。此外，A452 将细胞从抗凋亡（AKT 和 ERK）途径转移到促凋亡（p38）途径。A452 通过增加 γH2AX 和激活检查点激酶 Chk2 引发 DNA 损伤。A452 诱导细胞迁移和侵袭的抑制。有趣的是，A452 上调了 PD-L1 的表达，PD-L1 调节 T 细胞中的 PD-1 抑制途径。总的来说，我们的结果表明，A452 作为抗癌剂比 ACY-1215 更有效。因此，针对 HDAC6 的治疗可能代表一种新的癌症治疗策略，而与 p53 突变状态无关。
