转录调节因子PHF14通过调控TGF-β信号通路促进非小细胞肺癌转移的分子机制研究

Non-small cell lung carcinoma (NSCLC) is one of the most common malignant tumor with the highest morbidity and mortality worldwide. Metastasis is the major cause of death from cancer, even with constant investigations, therefore prevention and destruction of cancer metastasis is still a rough topic in basic and clinical cancer research. TGF-β signaling pathway activation is associated with tumor metastasis. Previously, we found that a transcriptional regulatory factor PHF14 was up-regulated by TGF-β pathway long-term activation. And analysis of NSCLC clinical data indicate that expression of PHF14 was up-regulated in NSCLC, meanwhile, PHF14 expression was correlates with poor prognosis of NSCLC patients, suggesting that PHF14 was involved in NSCLC metastasis. Furthermore, we found that ectopic expression of PHF14 promoted NSCLC invasion and metastasis in vitro and in vivo. Our research suggests the pivotal role of PHF14 in NSCLC metastasis. By using chromosomal immunoprecipitation and other methods, we identified that PHF14 maintained the sustained activation of TGF-β signaling through inducing histone modification H4R3me2s on promoters of SMAD7, Smurf1 and Smurf2 genes, and suppressing their transcription, which are negative regulators of TGF-β signaling, by recruiting arginine methyltransferase PRMT5. In the current project, we will investigate the mechanisms of PHF14-induced NSCLC metastasis by recruiting in vitro, in vivo assays and pathological analysis. Our work may help to identify a novel diagnostic marker and a therapeutic target for metastatic NSCLC.

非小细胞肺癌是发病率最高，死亡病例数最多的肿瘤。肿瘤转移是肿瘤致死的主要原因，因此寻找调控肿瘤转移的关键分子对肺癌的诊断治疗具有重要意义。TGF-β信号通路持续激活与肿瘤转移密切相关，申请者前期研究发现TGF-β长时间激活诱导转录调节因子PHF14表达升高，而且PHF14在肺癌中表达水平升高，并与肺癌患者较差的预后相关，提示PHF14可能与肿瘤转移相关。进一步预实验结果显示PHF14具有促进肺癌侵袭和转移的重要生物学功能。结合染色体免疫共沉淀等研究方法，我们发现PHF14结合在TGF-β负调控因子SMAD7、Smurf1和Smurf2基因启动子区域，并招募精氨酸甲基转移酶PRMT5促进这些区域发生组蛋白修饰H4R3me2s，抑制相关基因表达，维持TGF-β持续激活。本研究将在此基础上深层次解析PHF14促进肺癌转移的分子机制，并结合临床，为转移性非小细胞肺癌提供新的诊断标记物和治疗靶点。

肺癌是当今发病率最高、死亡病例数最多的恶性肿瘤。肺癌转移是导致肺癌患者死亡的主要原因。超过一半的肺癌患者初诊时即已发生对侧转移、远处转移等恶性进展，并最终导致肺癌患者的不良预后。因此，本研究围绕阐明肺癌转移的关键分子机制展开研究，旨在寻找潜在的诊疗靶点，为转化医学研究提供理论依据。本研究阐明了：1. 激活型AKT上调的长非编码RNA VAL通过与中间纤维蛋白Vimentin结合，维持其稳定，促进肺腺癌系统转移的生物学功能和分子机制；2. 肺癌中扩增的RFC4结合并维持Notch胞内段NICD1稳定及Notch信号通路异常激活，促进肺癌转移和干细胞特性的生物学功能和分子机制；3. PHF14高表达促进DNMT3B介导的SMAD7 DNA甲基化和转录抑制，进而促进TGF-β信号激活和肺腺癌转移的生物学功能和分子机制。从表观遗传学调控、蛋白翻译后修饰等层面揭示了AKT、Notch、TGF-β信号通路介导肺癌转移的关键分子机制和潜在诊疗靶点。本项目计划目标已完成，相关研究成果发表2篇研究论文（Nat Commun. 2020；Nat Commun. 2021），另有1篇正在投稿。