结直肠癌（CRC）是一种严重危害人类健康的常见消化道肿瘤，由侵袭与迁移引起的并发症是导致患者死亡的主要原因之一。组蛋白去甲基化酶KDM5B调控H3组蛋白去甲基化修饰与多种肿瘤的增殖、分化、侵袭与迁移等相关。研究显示泛素化特异性蛋白酶33（USP33）通过Slit2-Robo信号通路介导结直肠癌细胞的侵袭与迁移，但KDM5B与USP33在结直肠癌中的调控关系尚不清楚。本实验已有工作基础表明KDM5B在人结直肠癌组织和细胞中的表达显著升高，同时可抑制USP33的表达，这提示KDM5B可能通过调控USP33促进结直肠癌细胞的侵袭与迁移。本项目拟在前期工作基础上，从细胞、分子、动物三个层面阐明KDM5B与USP33基因上游调控序列直接结合，通过改变组蛋白H3甲基化修饰水平以及染色质结构重塑进而调控USP33的表达，明确KDM5B在促进结直肠癌侵袭与迁移的作用机制，为结直肠癌治疗提供新的潜在靶点。

Colorectal cancer (CRC) is one of common gastrointestinal tumor with a serve harm to human health, the complications caused by invasion and migration is one of main reason resulting in death of patients with colorectal cancer. Histone demethylase KDM5B is an important histone modification enzyme, which involved in tumors proliferation, differentiation, invasion and migration by demethylating of histone H3. Studies have shown that ubiquitin specific protease 33 (USP33) mediated invasion and migration of colorectal cancer cells through Slit2-Robo signaling pathway. However, the regulation mechanism of KDM5B and USP33 is still unclear in colorectal cancer. Our previous data demostrated that KDM5B is significantly overexpressed in human colorectal cancer tissues and cells. Meanwhile, it can directly repress the transcription of USP33, which suggested KDM5B may mediate the invasion and migration process of colorectal cancer cells via USP33 regulation. Therefore, in this project, our aim is to reveal the molecular mechanism of KDM5B promotes CRC invasion and migration by directly binding to USP33 upstream regulatory sequence and causes the chromatin structure remodeling with histone H3 methylation modification changes in the cellular, molecular, and animal levels. This project will provide a new potential target for the treatment of colorectal cancer.