MYC调控的肿瘤特异超增强子通过激活LGR5促进结直肠癌转移及复发

结直肠癌（CRC）中LGR5是一个重要的肿瘤起始细胞标记，其表达对CRC转移灶的建立是必需的，但LGR5在肿瘤中被激活的机制还不清楚。我们发现CRC中LGR5的转录可能被一个肿瘤特异的远端超增强子（SE）驱动，而且其高表达可预测CRC高复发。经典癌转录因子MYC在LGR5 SE区域高度富集，且其表达与LGR5在CRC中正相关。全基因组范围内MYC占据了91%的SE，并与Mediator等多个SE特征标记都高度重合。因此我们提出假设：CRC中LGR5转录被一个肿瘤特异的远端SE激活，进而增强肿瘤起始细胞干性并促进CRC转移及复发；机制上MYC通过招募Mediator调控包括LGR5位点的广谱SE功能。本项目将使用基因编辑、染色质免疫共沉淀和鼠转移模型等工具，阐明MYC调控的SE驱动LGR5表达参与CRC转移及复发的机制，为完善SE调控机器图景及优化靶向肿瘤起始细胞的治疗策略提供更多依据。

LGR5 is an important tumor-initiating cell marker in colorectal cancer (CRC). Its expression is indispensable for the establishment of CRC metastases, but the mechanisms underlying LGR5 activation in tumors still remain unclear. We found that LGR5 transcription may be driven by a tumor-specific distal super-enhancer (SE) in CRC, and its higher expression can predict worse CRC recurrence. Classical oncogenic transcription factor MYC is highly enriched in the LGR5 SE region, and its expression correlates with LGR5 in CRC. At genome-wide level, MYC occupies more than 90% of all SEs, and is highly correlated with multiple SE signatures including Mediator. Thus, we propose the hypothesis: the transcription of LGR5 is activated by a tumor-specific distal SE in CRC, thereby enhancing stemness of tumor-initiating cells and promoting CRC metastasis and recurrence; mechanistically, MYC controls global SE function including LGR5 locus through recruiting Mediator complex. This project will use tools such as gene editing, chromatin immunoprecipitation, chromosome conformation capture, and mouse metastasis models to clarify the mechanism by which MYC-regulated SE drives LGR5 expression to foster CRC metastasis and recurrence, providing more evidence for completing landscape of SE-regulating machinery and improving therapeutic strategies targeting tumor-initiating cells.