Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, PR China.
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
Cell Death Dis. 2023 Oct 24;14(10):697. doi: 10.1038/s41419-023-06225-w.
Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments.
越来越多的证据表明，DNA 甲基化在鼻咽癌（NPC）的发生和发展中起着重要作用。DNAJA4 在 NPC 中呈高甲基化，但其在调节 NPC 进展中的作用尚不清楚。在这里，我们揭示了 DNAJA4 的启动子在 NPC 组织和细胞中呈高甲基化，其表达下调。过表达 DNAJA4 显著抑制 NPC 细胞的迁移、侵袭和 EMT 表型，显著抑制体内腹股沟淋巴结转移和肺转移定植，而不影响 NPC 细胞的活力和增殖能力。机制上，DNAJA4 通过招募 PSMD2 促进 MYH9 蛋白通过泛素蛋白酶体途径降解。此外，在 NPC 细胞中转染 MYH9 可逆转 DNAJA4 对 NPC 细胞迁移、侵袭和 EMT 的抑制作用。临床上，DNAJA4 水平低表明 NPC 患者预后不良，远处转移的概率增加。综上所述，DNAJA4 是 NPC 侵袭和转移的关键驱动因素，DNAJA4-PSMD2-MYH9 轴可能包含 NPC 治疗的潜在靶点。
