YAP1调控lncRNA的m6A修饰而促进结肠癌侵袭转移的机制

Hippo-YAP通路与肿瘤发生发展的关系非常密切。我们前期发现，YAP1是结肠癌中重要的癌基因。YAP1调控的下游靶分子中除了基因之外，还有lncRNA。YAP1可通过下游的linc00152、MALAT1而促进结肠癌细胞的增殖与侵袭转移。我们新近发现YAP1可调控细胞m6A修饰谱，可与m6A writer METTL3结合，m6A修饰的RNA可促进YAP1入核并与METTL3结合。基于此，我们提出科学假设，YAP1可通过调控lncRNA的m6A修饰，影响lncRNA的代谢，发挥一系列生物学效应，从而促进结肠癌细胞侵袭与转移。我们还将针对该机制设计靶向策略，在小鼠模型中考察是否可抑制结肠癌转移。YAP1调控lncRNA m6A修饰可能是其发挥生理学功能的一个新的途径，研究该途径为结肠癌的转化研究提供新的、重要的研究材料。

The Hippo pathway is a highly conserved signaling pathway across higher-order vertebrates that modulates key target genes to regulate a multitude of biological processes including cellular proliferation, survival, differentiation, cellular fate determination, organ size, and tissue homeostasis. The link between the Hippo pathway and cancer development has been intensively studied in recent years..Yes-associated protein 1 (YAP1) is an effector of Hippo pathway, which is critical for regulating organ size, cell proliferation and tumor growth in mammals. We previous reported the relationship between YAP1 and tumorigenesis and metastasis of colorectal cancer. Positive YAP1 expression can statistically contribute to poor overall survival and disease-free survival in patients with colorectal carcinoma. We identified the downstream genes of YAP1, and found that, besides mRNAs, multiple lncRNAs are regulated by YAP1. .YAP1 can promoter tumorigenesis and metastasis of colorectal cancer through modulating lncRNAs such as linc00152 and MALAT1. Both of them are identified as oncogenic lncRNAs in colorectal cancer. .We recently discovered that YAP1 can modulate the cellular m6A epitranscriptomes of colon cancer cells. YAP1 can interact with METTL3 (a m6A writer) in the cellular nucleus. Adding the m6A modified RNA into the cells can promote YAP1’s location in the nucleus and facilitate its interaction with METTL3..Based on these findings, we suggest a hypothesis in this proposal that YAP1 promotes colon cancer invasion and metastasis through modulating m6A modification of lncRNAs such as linc00152 and MALAT1..In this study, we will dissect the molecular mechanisms underlying how YAP1 modulates the m6A modification of lncRNA, and the effect of this modification on lncRNA metabolism; and how the YAP1-lncRNA axis could promote metastasis of colon cancer cells through controlling FSCN1 and S100A8. Both of them are downstream targets of linc00152. FSCN1 proteins organize F-actin into parallel bundles, and are required for the formation of actin-based cellular protrusions, playing a critical role in cell migration, motility, adhesion and cellular interactions. S100A8 is a cytokine secreted by multiple cells and is crucial for inflammation process as well as tumor metastasis. We will test the effect of targeting the YAP1-lncRNA axis and m6A modification mechanism in mouse model of colon cancer metastasis..This study will provide new insight into the potential use of YAP1-lncRNA and m6 modification for the development of new treatment strategies for colorectal tumorigenesis.