RAD6B通过组蛋白翻译后修饰调节Snail1转录及结肠癌转移机制的研究

结直肠癌远处转移导致病人预后差且极易复发，但结直肠癌转移的具体机制还不清楚。我们前期通过基因芯片分析和TCGA数据库发现RAD6B与结直肠癌转移密切相关，且在TNM分期IV期结肠癌病例中显著高表达；通过体外实验证实RAD6B通过调节EMT促进结肠癌转移；进一步研究发现，在结肠癌中，NFκB既上调RAD6B表达，又可结合在snail1启动子区域，而该区域附近有明显的组蛋白H3甲基化。结合RAD6B在基因转录中的作用，我们提出科学假说:“在结肠癌中，RAD6B表达受NFκB调节，高表达的RAD6B泛素化修饰H2B，进而增加Snail1启动子区域组蛋白H3K4Me3和H3K79Me3水平，从而协同NFκB促进Snail1的转录，抑制下游E-cadherin的表达并促进结肠癌转移”。本研究拟通过临床样本、小鼠荷瘤模型和CHIP等加以证实，为临床结直肠癌的治疗提供理论依据。

Colorectal cancer often undergoes distant metastasis, leading to poor prognosis and recurrence. However, the molecular mechanism of colorectal cancer metastasis remains to be elucidated. In our previous research, through IPA analysis, we found that RAD6B is closely related to colon cancer metastasis, and it is significantly overexpressed in stage 4 cases. Preliminary studies have demonstrated that RAD6B can promote metastasis of colorectal cancer by participating in EMT; Further study showed that NFκB could promote the expression of RAD6B and bind to the promoter region of snail1 in colon cancer, and histone H3 near this region is markedly methylated. Combined with the role of RAD6B in gene transcription, we have proposed that RAD6B increases the methylation level of histone H3 in the snail1 promoter region through ubiquitination of histone H2B, leading to increased transcription of snail1. Increased snail1 further inhibits E-cadherin expression and promotes colon cancer cell invasion and metastasis. In further research, we will conduct experiments based on clinical samples, mouse tumor-bearing models, CHIP, and small molecule inhibitors to provide theoretical evidence for the treatment of colorectal cancer.