KDM4B通过调控VEGF组蛋白甲基化促进肾癌血管生成及侵袭转移的相关分子机制研究

Anti-VEGF signaling pathway targeted drugs have been widely used in advanced renal cell carcinoma (RCC) as first-line and second-line therapy. However, there were considerable differences in the response of different patients to drugs. And the effective molecular biomarkers which can accurately evaluate the therapeutic effect of these targeted drugs to RCC are still lacking to date. Therefore, it is of important significance to explore new related biomarkers for RCC individualized treatment. In previous study, we found the histone demethylase KDM4B were highly expressed in RCC tumor tissues compared with adjacent normal tissues and confirmed the abnormal high expression in the Cancer Genome Atlas (TCGA) database. Further analysis and research suggest the expression level of KDM4B has significantly negative correlation with the overall survival time and progression-free survival time of RCC patients, and KDM4B was regulated by HIF-1α in RCC. At the same time, we found KDM4B could promote the expression of VEGF via regulating the methylation level of VEGF histone based on the analysis results of RNA-Seq, TCGA database and ChIP-qPCR assay. In this project, we aim to evaluate the relationship between the expression level of KDM4B and the prognosis of RCC patients as well as the therapeutic effect of anti-VEGF signaling pathway targeted drugs in advanced RCC patients. Furthermore, using a series of in vitro and in vivo experiments, bioinformatic analysis, we will clarify the effect of KDM4B on RCC angiogenesis, invasion and metastasis. Moreover, we will explore the molecular mechanisms of KDM4B regulating RCC angiogenesis. Our researches would provide guidance and experimental foundation for the selection of anti-VEGF signaling pathway targeted drugs and individualized treatment of RCC.

阻断VEGF信号通路类靶向药物已广泛用于晚期肾癌的治疗，但不同患者对药物的反应存在差异，尚缺乏能够准确评估此类靶向药物对肾癌疗效的有效分子标志物，因此寻找新的相关生物学靶点对于肾癌个体化治疗具有重要意义。我们前期研究发现组蛋白去甲基化酶KDM4B在肾癌组织中异常高表达，其表达水平与肾癌患者总生存时间及无进展生存时间呈负相关，且KDM4B受到HIF-1α调控。通过测序分析、TCGA数据库验证及ChIP-qPCR实验证实，肾癌中KDM4B可调控VEGF组蛋白甲基化水平进而促进VEGF表达。本项目拟评估KDM4B在肾癌组织中表达水平与患者预后及VEGF信号通路靶向药物疗效的关系；并进一步通过一系列体内外实验、生物信息学分析明确KDM4B对肾癌血管生成及侵袭转移的影响，深入探讨KDM4B调控肾癌血管生成的相关分子机制。以期为肾癌患者VEGF信号通路类靶向药物的选择提供个体化的指导信息与实验依据。

抗血管生成靶向药物已广泛用于晚期肾癌的治疗，但不同患者对药物的反应存在差异，尚缺乏能够准确评估此类靶向药物对肾癌疗效的有效分子标志物，因此寻找新的相关生物学靶点对于肾癌个体化治疗具有重要意义。在本项目研究中我们发现组蛋白去甲基化酶KDM4B在肾癌组织中异常高表达，其表达水平与肾癌患者总生存时间、无进展生存时间及抗血管生成靶向药物疗效均呈负相关。并通过一系列体内外实验、生物信息学分析证明KDM4B能够促进肾癌细胞增殖、血管生成及侵袭转移。进一步阐明其分子机制是KDM4B能够调控长链非编码RNA PVT1基因启动子区域组蛋白H3K9甲基化水平，上调PVT1表达，而PVT1能够稳定HIF2α蛋白，减少HIF2α蛋白泛素化降解，进而上调HIF2α信号通路，包括VEGF信号通路，促进肾癌细胞增殖、血管生成和侵袭转移。与此同时，PVT1上游增强子中含有低氧反应元件，HIF2α能够与之结合促进lncRNA PVT1表达，二者形成正反馈调控，促进肾癌发生发展。本项目的研究成果有助于为肾癌患者抗血管生成靶向药物的选择提供个体化的指导信息与实验依据。