基于超级增强子的HOXB8核心转录调控环路促进骨肉瘤转移机制的研究

骨肉瘤是最常见的青少年原发恶性骨肿瘤，转移是其致死的主要原因。我们前期已发现骨肉瘤转移的关键调控因子，预实验鉴定了骨肉瘤转移和非转移超级增强子（SE）图谱及驱动基因，其中HOXB8是关键的转移相关SE驱动基因。下调HOXB8能降低转移相关SE驱动基因表达，显著抑制骨肉瘤转移。ChIP-seq结果显示HOXB8与FOSL1彼此调控，共同结合转移相关SE区域。GSK-J4能够抑制HOXB8表达。据此提出科学假说： HOXB8和FOSL1等转录因子组成促骨肉瘤转移核心转录调控环路，抑制关键转录因子HOXB8可以破坏SE介导的转录调控环路，进而阻断骨肉瘤转移。本项目拟阐明HOXB8核心转录调控环路对靶基因的调控机制，探究SE在核心转录调控环路形成中的功能，并探索通过药物干预HOXB8核心转录调控环路对骨肉瘤转移的治疗作用。本项目实施有助于阐明骨肉瘤转移机制，为骨肉瘤转移的治疗找到新策略。

Osteosarcoma is the most common primary malignant tumor in adolescent, and distant metastasis is the main cause of death. We have discovered some critical regulation factors of metastasis previously. Recently, we have established the landscapes of super enhancers(SE) of osteosarcoma with and without metastasis and found HOXB8 is the crucial metastasis related SE-driving gene. Knocking down of HOXB8 could suppress the expression metastasis-specific SE driving genes and suppress the metastasis of osteosarcoma significantly. The result of ChIP-seq indicate that HOXB8 and FOSL1 could bind the enhancer of themselves and each other and bind similar regulatory domain the metastasis specific SE driving genes. GSK-J4 could inhibit the expression of HOXB8. So, we hypothesis: HOXB8 and FOSL1 compose the core transcription regulatory circuitry(CRC)of metastasis of osteosarcoma, inhibition of critical transcription factor HOXB8 could destroy the core transcription regulatory circuitry and prevent the metastasis of osteosarcoma. We plan to illuminate the regulation mechanism of HOXB8-cored CRC on the target genes and the function of SE on the formation of HOXB8-cored CRC; go furtherly to discover efficiency of the drugs to interfering the HOXB8-cored CRC and preventing metastasis of osteosarcoma. This research will help to uncovering the mechanism of metastasis and find the new strategy to treat metastasis of osteosarcoma.