SMYD3/YBX1调控CD44可变剪切促进结直肠癌侵袭转移的机制研究

组蛋白修饰异常在癌症发生演进中发挥关键作用，但组蛋白甲基转移酶SMYD3促进结肠癌转移的分子机制不详。我们前期生物信息学分析发现SMYD3在结肠癌高表达，功能实验证明SMYD3促肿瘤细胞运动侵袭；免疫共沉淀及质谱分析出SMYD3与癌基因样剪切因子YBX1形成复合体；RNA-seq及差异剪切事件分析出SMYD3广泛调控肿瘤基因可变剪切，并涉及细胞黏附及多种信号通路；其中SMYD3引起包含v3/v6外显子的CD44剪切变异体明显上调,该剪切变异体常作为肿瘤侵袭转移标志。我们提出假说：“SMYD3协同剪切因子YBX1调控黏附因子CD44可变剪切，可能是结肠癌侵袭转移的机制之一”，探讨一个新的SMYD3-YBX1蛋白复合体通过组蛋白修饰和可变剪切的协同机制调控CD44剪切变异体的分子基础，以及SMYD3/YBX1-CD44v通路在结肠癌转移中的作用，为抑制结肠癌侵袭转移提供新的分子靶点和实验依据。

Aberrancies in histone modification play a critical role in tumorigenesis and malignant progression, but it remains unclear whether and how the histone methyltransferase SMYD3 contributes to colorectal cancer metastasis. We have found that high expression of SMYD3 in CRC correlates with cancer metastasis by bioinformatics analysis and vitro experiment. Co-immunoprecipitation and mass spectrometry indicate that SMYD3 may form a novel protein complex with YBX1, which is a carcinogenic splicing factor in various types of cancer. RNA- Sequencing and differential splicing event analysis reveal that SMYD3 widely regulates alternative splicing of tumor genes that involved in cell adhesion and multiple signaling pathways. CD44 is one of the important cell adhesion factors, the overexpression of SMYD3 result in a significant up-regulation of the CD44 splicing variant containing the exon of v3 or v6, which is known as the marker for invasion and metastasis. We propose that the cooperation of SMYD3 and YBX1 regulate alternative splicing of CD44, which may be crucial for invasion and metastasis of CRC. We will further explore the molecular mechanism of the novel SMYD3-YBX1 protein complex regulating the expression of CD44 splicing variants through the histone modification and alternative splicing, and define the effect of SMYD3/YBX1-CD44v pathway in colorectal cancer metastasis. Together, these findings may identify promising molecular targets to inhibit invasion and metastasis in CRC patients.