Mechanism of tumorigenesis by abnormal modification and regulation of intracellular molecules

在将生物信息从DNA转化为RNA和蛋白质的过程中，这些分子会根据细胞条件进行化学修饰和调节。除了DNA序列本身，整个过程通常被称为广义的表观遗传调控，包括胞嘧啶甲基化和染色质，以及蛋白质的翻译后修饰。由于基因功能在DNA和蛋白质水平上都受到控制，这些机制在恶性转化细胞和癌细胞中往往是失调的。本研究从肿瘤发生的生理和病理角度，重点研究了DNA甲基化和染色质的转录调控和蛋白质的修饰和降解两种调控机制。甲基CpG结合域蛋白MBD1以DNA甲基化介导的方式抑制肿瘤细胞中抑癌基因的转录。我们发现MBD1至少与两个组蛋白甲基转移酶复合体相互作用，即SUV39H1-HP1异色复合体和MCAF1-SETDB1等染复合体，以实现基于DNA甲基化的基因抑制。在本研究中，我们首次确定MCAF1和MCAF2是一个新的表观遗传调节蛋白家族。此外，MBD1与甲基嘌呤-DNA糖基酶相互作用，将染色质中的DNA甲基化和碱基切除修复联系起来。在蛋白质修饰方面，我们报道了Hect结构域泛素连接酶hHYD泛素化DNA拓扑异构酶II结合蛋白，用于DNA损伤反应。也有报道称，PML核体参与了c-fos基因的血清反应转录，血清反应因子(SRF)受SUMO-1的调节。同样，参与化学致癌和低氧诱导转录的芳烃受体核转运体(ARNT)也受到相扑结合系统的调控。

In conversion of biological information from DNA to RNA and protein, these molecules are chemically modified and regulated in response to cellular conditions. The whole processes except for the DNA sequence itself are often called as epigenetic regulation in a broad sense, which includes cytosine methylation and chromatin, and posttranslational modification of proteins. Since gene function is controlled at the both DNA and protein levels, these mechanisms are frequently dysregulated in malignantly transformed and cancer cells. This research project has focused on the two regulatory mechanisms, (1) transcriptional regulation by DNA methylation and chromatin, and (2) protein modification and degradation, from the viewpoint of physiological and pathological roles in carcinogenesis. Methyl-CpG binding domain protein MBD1 represses transcription from tumor suppressor genes in cancer cells in DNA methylation-mediated manner. We found that MBD1 interacts with at least two histone methyltransferase complexes, Suv39h1-HP1 heterochromatic complex and MCAF1-SETDB1 euchromatic complex, for DNA methylation-based gene repression. During this study, we first identified MCAF1 and MCAF2 as a new epigenetic regulator family of proteins. Further, MBD1 interacts with methylpurine-DNA glycosylase to link DNA methylation and base excision repair in chromatin. Regarding protein modification, we reported that HECT-domain ubiquitin ligase hHYD ubiquitinates DNA topoisomerase II-binding protein for DNA damage response. It was also reported that PML-nuclear bodies are involved in serum response transcription of c-fos gene, and that serum response factor (SRF) is modulated by SUMO-1. Similarly, aryl hydrocarbon receptor nuclear transporter (ARNT), which is involved in chemical carcinogenesis and hypoxia-induced transcription, is modulated by SUMO conjugation system.