Cheng Yingduan, Wang Yi, Li Jiong, Chang Insoon, Wang Cun-Yu
The Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, California, USA.
Oncotarget. 2017 Jan 10;8(2):1972-1982. doi: 10.18632/oncotarget.14081.
Recent findings on the existence of oncogenic fusion genes in a wide array of solid tumors, including head and neck squamous cell carcinoma (HNSCC), suggests that fusion genes have become attractive targets for cancer diagnosis and treatment. In this study, we showed for the first time that a read-through fusion gene JMJD7-PLA2G4B is presented in HNSCC, splicing neighboring jumonji domain containing 7 (JMJD7) and phospholipase A2, group IVB (PLA2G4B) genes together. Ablation of JMJD7-PLA2G4B significantly inhibited proliferation of HNSCC cells by promoting G1 cell cycle arrest and increased starvation-induced cell death compared to JMJD7-only knockdown HNSCC cells. Mechanistically, we found that JMJD7-PLA2G4B modulates phosphorylation of Protein Kinase B (AKT) to promote HNSCC cell survival. Moreover, JMJD7-PLA2G4B also regulated an E3 ligase S-phase kinase-associated protein 2 (SKP2) to control the cell cycle progression from G1 phase to S phase by inhibiting Cyclin-dependent kinase inhibitor 1 (p21) and 1B (p27) expression. Our study provides novel insights into the oncogenic control of JMJD7-PLA2G4B in HNSCC cell proliferation and survival, and suggests that JMJD7-PLA2G4B may serve as an important therapeutic target and prognostic marker for HNSCC development and progression.
近期在包括头颈部鳞状细胞癌（HNSCC）在内的多种实体瘤中发现致癌融合基因，这表明融合基因已成为癌症诊断和治疗的有吸引力的靶点。在本研究中，我们首次表明HNSCC中存在一种通读融合基因JMJD7-PLA2G4B，它将相邻的含jumonji结构域7（JMJD7）基因和IVB组磷脂酶A2（PLA2G4B）基因剪接在一起。与仅敲低JMJD7的HNSCC细胞相比，敲除JMJD7-PLA2G4B通过促进G1期细胞周期停滞显著抑制HNSCC细胞增殖，并增加饥饿诱导的细胞死亡。从机制上讲，我们发现JMJD7-PLA2G4B调节蛋白激酶B（AKT）的磷酸化以促进HNSCC细胞存活。此外，JMJD7-PLA2G4B还调节E3连接酶S期激酶相关蛋白2（SKP2），通过抑制细胞周期蛋白依赖性激酶抑制剂1（p21）和1B（p27）的表达来控制细胞周期从G1期到S期的进程。我们的研究为JMJD7-PLA2G4B在HNSCC细胞增殖和存活中的致癌调控提供了新的见解，并表明JMJD7-PLA2G4B可能作为HNSCC发生和发展的重要治疗靶点和预后标志物。
