Department of Microbial and Biochemical Pharmacy, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Eur J Pharmacol. 2019 Feb 15;845:16-23. doi: 10.1016/j.ejphar.2018.12.030. Epub 2018 Dec 21.
Triple-negative breast cancer (TNBC) shows highly aggressive clinical behaviors and poor prognosis compared to other breast cancer subtypes. Histone deacetylases (HDACs) can regulate the progression of various cancers, but the role of HDAC8 in TNBC remains unexplored. Here, we found that HDAC8 enhanced the in vitro migration abilities of breast cancer cells. Targeted inhibition of HDAC8 via si-HDAC8 and its selective inhibitor PCI34051 could suppress the migration of cells. In TNBC cells, HDAC8 stabilized the expression and increased the nuclear localization of YAP, a major downstream effector of Hippo pathway. While silencing YAP could attenuate HDAC8 triggered migration of TNBC cells. Mechanistically, HDAC8 suppressed the phosphorylation of YAP, which was related to its cytoplasmic sequestration degradation. Our data revealed that HDAC8 could trigger the migration of TNBC cells via regulation of Hippo-YAP signals, suggesting that HDAC8 might be a potential target for TNBC therapy.
三阴性乳腺癌（TNBC）与其他乳腺癌亚型相比，表现出高度侵袭性的临床行为和不良预后。组蛋白去乙酰化酶（HDACs）可以调节多种癌症的进展，但 HDAC8 在 TNBC 中的作用仍未被探索。在这里，我们发现 HDAC8 增强了乳腺癌细胞的体外迁移能力。通过 si-HDAC8 和其选择性抑制剂 PCI34051 靶向抑制 HDAC8 可以抑制细胞的迁移。在 TNBC 细胞中，HDAC8 稳定了 YAP 的表达并增加了 Hippo 通路的主要下游效应物 YAP 的核定位。而沉默 YAP 可以减弱 HDAC8 触发的 TNBC 细胞迁移。在机制上，HDAC8 抑制了 YAP 的磷酸化，这与 YAP 的细胞质隔离降解有关。我们的数据表明，HDAC8 可以通过调节 Hippo-YAP 信号触发 TNBC 细胞的迁移，提示 HDAC8 可能是 TNBC 治疗的潜在靶点。
