Nature Cell Biology | 发现mRNA甲基化调控实体瘤膀胱癌的发生机制
RNA甲基化是表观遗传学领域的研究热点，也是Nature, Science级别文章的宠儿。随着RNA甲基化研究的深入，一类新的RNA甲基化修饰方式再次掀起科学界的热点话题, 它就是5-甲基胞嘧啶（m5C） RNA甲基化修饰，m5C修饰是mRNA上分布广泛的碱基修饰形式之一，但对于进入细胞质内的含有m5C修饰的mRNA的命运决定及其在生理和病理中的调控作用目前尚不清楚。
膀胱癌是指发生在膀胱黏膜上的恶性肿瘤。是泌尿系统最常见的恶性肿瘤，也是全身十大常见肿瘤之一。常见的是膀胱尿路上皮癌，约占膀胱癌患者总数的90%以上，通常所说的膀胱癌就是指膀胱尿路上皮癌。中科院北京基因组研究所杨运桂团队联合中山大学肿瘤医院周芳坚团队、谢丹团队和中科院生化细胞所黄旲团队合作研究，发现m5C通过细胞质内新结合蛋白YBX1调控mRNA的稳定性，进而调控膀胱癌的增殖和转移。这一成果于2019.07.29发表在Nature Cell Biology上，文章题目为5-methylcytosine promotes pathogenesis of the bladder cancer through stabilizing mRNAs
文章中，研究团队首先绘制了膀胱癌组织中mRNA上的m5C单位点图谱，发现癌症通路相关基因的mRNA倾向于高甲基化修饰，随着膀胱癌分级、淋巴结转移的疾病进展，相关原癌基因mRNA m5C甲基化水平逐渐升高。利用Oligo-pull down结合质谱、蛋白解构技术和高通量测序技术发现了细胞质内新的m5C结合蛋白YBX1，W65是YBX1识别mRNA m5C的关键氨基酸，并且YBX1以m5C依赖的方式调控mRNA稳定蛋白ELAVL1的RNA结合能力。相比于癌旁组织，m5C甲基转移酶NSUN2和m5C结合蛋白YBX1在膀胱癌组织中高表达。进一步通过体内、体外小鼠成瘤和转移实验及高通量测序技术，证明了NSUN2和YBX1以m5C依赖的方式促进HDGF mRNA的稳定性并最终促进膀胱癌肿瘤的增殖和转移。
NSUN2/YBX1通过m5C介导调控HDGF mRNA稳定性促进膀胱癌的发生
这项研究揭示了mRNA甲基化调控实体瘤膀胱癌发生的分子机制，为膀胱癌预防和治疗提供了新的研究方向；在新的层面上揭示了mRNA 甲基化修饰作为新的调控手段调控肿瘤的发生，这种转录后修饰可能在其它肿瘤疾病中也可能发挥着重要作用。
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