PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing
PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing
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DOI：
10.1002/cam4.2115
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发表时间：
2019-05-01
期刊：
影响因子：
4
通讯作者：
He, Jie
中科院分区：
文献类型：
--
作者：
Mao, Shuangshuang;Li, Yuan;He, Jie
选择性剪接（AS）及其剪接因子对AS的调控在肿瘤中起着重要作用。植物同源结构域（PHD）-指状结构域蛋白PHF 5A是参与AS的关键剪接因子，已被证实在多形性胶质母细胞瘤和乳腺癌中发挥致癌作用，但其在肺癌中的生物学功能尚不清楚。本研究系统分析了PHF 5A在非小细胞肺癌（NSCLC）中的生物学功能及临床意义。我们发现PHF 5A在非小细胞肺癌肿瘤中的表达明显高于正常组织，无论是在TCGA数据集还是组织微阵列中。PHF 5A的上调与肺腺癌（LUAD）患者的总生存期（OS）呈负相关。功能丧失和功能获得实验证实PHF 5A作为一种癌基因蛋白，通过促进LUAD细胞增殖、迁移和侵袭，诱导细胞进入G 0/G1期，抑制顺铂诱导的细胞凋亡发挥作用。RNA-seq分析鉴定了许多PHF 5A导致AS失调的必需基因，包括细胞周期相关基因如SKP 2、CHEK 2、ATR和凋亡相关基因如API 5和BCL 2L 13。此外，普拉地那肽，一种PHF 5A的小分子抑制剂，以剂量依赖的方式抑制LUAD细胞增殖，并诱导AS的变化类似于PHF 5A敲低。总之，我们验证了PHF 5A通过AS在LUAD中发挥致癌作用，并建议PHF 5A可能作为一个潜在的药物靶点，具有良好的抗癌治疗效果。
Alternative splicing (AS) and the regulation of AS by splicing factors play critical roles in cancer. Plant homeodomain (PHD)-finger domain protein PHF5A, a critical splicing factor involved in AS, has been demonstrated to play an oncogenic role in glioblastoma multiforme and breast cancer, but its biological function in lung cancer remains unclear. In the present study, we systematically analyzed the biological function and clinical relevance of PHF5A in non-small cell lung cancer (NSCLC). We found that PHF5A was significantly upregulated in NSCLC tumors compared with normal tissues in both TCGA data set and tissue microarrays. Upregulation of PHF5A was negatively correlated to the overall survival (OS) of lung adenocarcinoma (LUAD) patients. Loss-of-function and gain-of-function experiments confirmed that PHF5A functioned as an oncoprotein by promoting LUAD cell proliferation, migration and invasion, inducing G0/G1 cell cycle progression and inhibiting cisplatin-induced apoptosis. RNA-seq analysis identified many essential genes whose AS was dysregulated by PHF5A, including cell cycle-associated genes such as SKP2, CHEK2, ATR and apoptosis-associated genes such as API5 and BCL2L13. Additionally, pladienolide, a small molecular inhibitor of PHF5A, inhibited LUAD cell proliferation in a dose-dependent manner and induced AS changes similar to PHF5A knockdown. In conclusion, we validated that PHF5A played an oncogenic role via AS in LUAD and suggested that PHF5A might serve as a potential drug target with a promising anticancer therapeutic effect.