Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, 410008, China.
Cell Death Dis. 2020 May 6;11(5):322. doi: 10.1038/s41419-020-2521-1.
HDAC7 plays a crucial role in cancers, and is the main drug target of several HDAC inhibitors. However, the role and mechanism of HDAC7 in nasopharyngeal carcinoma (NPC) are still unclear. In this study, we observed that HDAC7 was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM) tissues, HDAC7 expression levels were positively correlated with NPC progression and negatively correlated with patient prognosis, and HDAC7 knockdown dramatically inhibited the in vitro proliferation, migration, and invasion of NPC cells, and the growth of NPC xenografts in mice, indicating the HDAC7 promotes the oncogenicity of NPC. Mechanistically, HDAC7 promoted the in vitro proliferation, migration, and invasion of NPC cells by upregulating EphA2, in which miR-4465 mediated HDAC7-regulating EphA2, a direct target gene of miR-4465. We further showed that miR-4465 was significantly downregulated in the NPC tissues relative to NNM tissues, and inhibited the in vitro proliferation, migration, and invasion of NPC cells by targeting EphA2 expression. Moreover, we observed that the expressions of HDAC7, miR-4465, and EphA2 in NPC tissues were correlated. The results suggest that HDAC7 promotes the oncogenicity of NPC by downregulating miR-4465 and subsequently upregulating EphA2, highlighting HDAC7 as a potential therapeutic target for NPC.
HDAC7 在癌症中发挥着关键作用，是几种 HDAC 抑制剂的主要药物靶点。然而，HDAC7 在鼻咽癌（NPC）中的作用和机制尚不清楚。在本研究中，我们观察到与正常鼻咽黏膜（NNM）组织相比，HDAC7 在 NPC 组织中显著上调，HDAC7 表达水平与 NPC 进展呈正相关，与患者预后呈负相关，HDAC7 敲低显著抑制 NPC 细胞的体外增殖、迁移和侵袭，以及 NPC 异种移植在小鼠中的生长，表明 HDAC7 促进 NPC 的致癌性。在机制上，HDAC7 通过上调 EphA2 促进 NPC 细胞的体外增殖、迁移和侵袭，其中 miR-4465 介导 HDAC7 调节 EphA2，miR-4465 的一个直接靶基因。我们进一步表明，与 NNM 组织相比，miR-4465 在 NPC 组织中显著下调，并通过靶向 EphA2 表达抑制 NPC 细胞的体外增殖、迁移和侵袭。此外，我们观察到 NPC 组织中 HDAC7、miR-4465 和 EphA2 的表达相关。结果表明，HDAC7 通过下调 miR-4465 继而上调 EphA2 促进 NPC 的致癌性，突出了 HDAC7 作为 NPC 潜在治疗靶点的作用。
