化疗耐药是结直肠癌治疗的关键障碍之一。表观遗传调控肿瘤的化疗耐药已有广泛研究，但调控机制仍未完全明确。表观遗传“阅读器”BRD4是近年来发现的抗癌研究热门靶点，其抑制剂正在多种肿瘤中开展各期临床试验。然而，BRD4是否及如何参与肿瘤化疗耐药仍不清楚。我们前期研究发现，BRD4在化疗耐药肿瘤中的高表达介导了癌细胞的化疗耐药性，同时去泛素化酶UCHL3可能通过稳定BRD4调控该过程。本项目拟以结直肠癌为研究对象，阐明BRD4参与结直肠癌化疗耐药的上、下游调控新机理（上游转录因子-UCHL3-BRD4-下游基因表达特征簇）；利用UCHL3、BRD4均可靶向的优势，探讨新型逆转BRD4抑制剂抗性、化疗抗性/增敏化疗响应的治疗手段；明确UCHL3、BRD4作为预测结直肠癌患者化疗敏感性、复发风险的新型生物标志物的价值。本项目拟通过新机制的阐明，为结直肠癌的防治尤其是化疗耐药的逆转提供新靶点和新思路。

Chemo-resistance is one of the key obstacles for successful treatment of colorectal cancer. The involvement of epigenetic regulation in tumor chemo-resistance has been extensively studied, but the regulatory mechanisms are still largely elusive. Epigenetic "reader" BRD4 (bromodomain-containing protein 4) is found to be a promising anti-cancer target in recent years, and various inhibitors targeting BRD4 are currently under clinical developed in multiple cancer types. Whereas, whether and how BRD4 is involved in chemo-resistance remains largely unknown. Based on our previous studies, we found that high expression of BRD4 mediates chemo-resistance in colorectal cancer, and that deubiquitinase UCHL3 may regulate this process by stabilizing BRD4.This project intends 1) to clarify the upstream and downstream regulatory mechanism of BRD4 (transcription factor-UCHL3-BRD4-gene signature) which is involved in chemo-resistance of colorectal cancer; 2) to explore new therapeutic methods for reversing the drug resistance/re-sensitizing response of chemotherapy. 3) to evaluate/identify UCHL3 and BRD4 as new biomarkers for predicting chemo-resistance and recurrence risk in patients with colorectal cancer. This project attempts to provide new targets and new ideas for the prevention and treatment of colorectal cancer, especially the reversal of chemo-resistance.