BRD7抑制c-Myc蛋白泛素化促进结直肠癌发生发展的作用及机制研究

BRD7, as a tumor suppressor, plays important roles in multiple malignancies, such as nasopharyngeal carcinoma, breast cancer and lung cancer. However, our previous study of the BRD7 gene knockout mouse model for colorectal cancer (CRC) and the malignant biological behavior of CRC cells showed that BRD7 is able to promote CRC initiation and progression. Further studies showed that BRD7 interacts with c-Myc and enhances the protein stability of c-Myc through inhibition of c-Myc ubiquitination. Therefore, to elucidate the role and mechanism of BRD7 involved in the promotion of colorectal cancer initiation and progression through inhibition of c-Myc ubiquitination, this project aims to identify the structure basis for the interaction between BRD7 and c-Myc; confirm the role of BRD7 involved in the transcriptional regulation of c-Myc target genes through targeting c-Myc ubiquitination; elucidate the mechanism of BRD7 targeted regulation of c-Myc ubiquitination; clarify the role of BRD7 involved in the promotion of CRC initiation and progression via targeting c-Myc in vitro and in vivo; reveal the correlation and clinical significance of the expression of BRD7 and c-Myc in CRC by using the CRC tissue microarray, providing a theoretical foundation for the mechanism of BRD7 involved in CRC initiation and progression and the role of BRD7 as a promising therapeutic target.

BRD7在多种恶性肿瘤，如鼻咽癌、乳腺癌、肺癌中均发挥重要的抑癌功能。然而，前期我们通过BRD7-/-小鼠构建的结直肠癌变模型及细胞恶性生物学行为实验证实：BRD7在结直肠癌发生发展过程中发挥显著的促癌作用。进一步研究发现BRD7与c-Myc间存在蛋白交互作用，并通过抑制c-Myc蛋白泛素化增强其稳定性。因此，为阐明BRD7抑制c-Myc蛋白泛素化促进结直肠癌发生发展的作用及机制，本项目拟确定BRD7和c-Myc间蛋白交互作用的结构基础；明确BRD7通过靶向c-Myc蛋白泛素化参与其下游靶基因的转录调控过程；阐明BRD7靶向调控c-Myc蛋白泛素化过程的分子机制；分别从体外和体内水平明确BRD7通过靶向c-Myc促进结直肠癌的发生发展过程；利用结直肠癌组织芯片，明确BRD7、c-Myc等分子的表达相关性及临床意义，为阐明BRD7促进结直肠癌发生发展的分子机制及作为潜在治疗靶点奠定理论基础。

BRD7在多种恶性肿瘤中发挥重要的肿瘤抑制作用。然而，BRD7对结直肠癌(CRC)进展的影响仍不清楚。我们在前期工作中构建的BRD7基因敲除(BRD7−/−)和BRD7flox/flox(BRD7+/+)小鼠模型的基础上，建立了偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)诱导的小鼠结直肠癌模型。BRD7+/+小鼠对AOM/DSS诱导的结肠炎相关性结直肠癌高度易感，BRD7显著促进细胞增殖和细胞周期G1/S期进程，但对细胞凋亡无明显影响。此外，BRD7与c-Myc相互作用，并通过抑制其泛素蛋白酶体依赖的降解来稳定c-Myc。此外，在BRD7沉默的CRC细胞中恢复c-Myc的表达，可以在体内、外恢复细胞增殖、细胞周期进程和肿瘤的生长。此外，BRD7和c-Myc蛋白在结直肠癌患者中均显著上调，且这些蛋白的高表达与结直肠癌的临床分期和不良预后相关。综上，BRD7作为癌基因发挥作用，通过调节泛素蛋白酶体依赖的c-Myc蛋白稳定性从而促进结直肠癌的进展。靶向BRD7/c-Myc轴可能是治疗结直肠癌的一种潜在策略。