Wang Ying, Chen Wanyuan, Lian Jiayan, Zhang Haibo, Yu Bo, Zhang Minjun, Wei Fangqiang, Wu Jianhui, Jiang Jiaxiang, Jia Yongshi, Mo Fan, Zhang Shirong, Liang Xiaodong, Mou Xiaozhou, Tang Jianming
Department of Radiation Oncology, Zhejiang Provincial People' s Hospital, People' s Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
Cell Death Differ. 2020 Feb;27(2):695-710. doi: 10.1038/s41418-019-0381-y. Epub 2019 Jul 18.
Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1β to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1β, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1β isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1β in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.
长链非编码RNA（lncRNAs）在调控多种癌症的发生发展过程中发挥着重要作用。然而，特定lncRNAs在鼻咽癌（NPC）中的临床意义以及它们调控这种癌症的分子机制仍不清楚。在本研究中，我们发现lncRNA PVT1在NPC中上调，且在患者中这种上调与生存率降低相关。RNA测序显示，PVT1负责调控NPC细胞增殖并控制这些细胞中的缺氧相关表型。在皮下小鼠异种移植模型系统中，PVT1敲低降低了NPC细胞增殖、集落形成和肿瘤发生。我们进一步发现，PVT1作为染色质修饰因子KAT2A的支架，介导组蛋白3赖氨酸9乙酰化（H3K9），招募核受体结合蛋白TIF1β以激活NF90转录，从而增加HIF-1α稳定性并促进NPC细胞中的恶性表型。NF90或HIF-1α的过表达恢复了因PVT1或KAT2A缺失而停止增殖的细胞中的增殖。相反，活性KAT2A或TIF1β的过表达促进了PVT1介导的NF90转录增加以及HIF-1α稳定性和细胞增殖增加，但KAT2A乙酰转移酶活性缺陷突变体或缺乏H3K9ac结合位点的TIF1β亚型则无此作用。PVT1敲低通过抑制H3K9ac与TIF1β之间的结合增强了NPC细胞的放射增敏作用。综上所述，我们的结果表明，PVT1通过激活KAT2A乙酰转移酶和稳定HIF-1α在恶性NPC中发挥致癌作用并在放射敏感性中起重要作用。
