超级增强子MYCNOS-SE招募转录因子FOXP1调控MYCNOS/MYCN/HES1通路参与小细胞肺癌化疗耐药的机制研究

耐药是导致小细胞肺癌（SCLC）患者化疗失败和预后不良的重要原因。我们前期利用H3K27ac的ChIP-seq技术结合关联分析，在SCLC耐药细胞H69AR中发现MYCNOS-SE等45个可能与耐药相关的超级增强子；生信分析和细胞实验确定FOXP1可能是MYCNOS-SE参与SCLC耐药的主要转录因子，FOXP1能调控MYCNOS表达，MYCNOS是MYCN的反义链，下调MYCN抑制NOTCH通路中HES1表达，细胞对化疗药物敏感性增加。我们由此提出MYCNOS-SE通过招募转录因子FOXP1，调控MYCNOS/MYCN/HES1通路，参与SCLC耐药的假说。本课题拟利用耐药细胞模型（H69AR/H446DDP）和SCLC组织标本，结合ChIP-PCR、荧光素酶等技术，进一步明确MYCNOS-SE参与SCLC耐药的作用及机制，通过本项目研究，为阐明SCLC化疗耐药的分子机制提供科学依据。

Chemoresistance is the major cause of chemotherapy failure and poor prognosis in small cell lung cancer (SCLC). Our previous study demonstrated that 45 drug resistance related super-enhancers including MYCNOS-SE combining with H3K27ac ChIP-seq and RNA seq. We confirmed transcription factor FOXP1 may be the main factor in MYCNOS-SE mediated SCLC chemoresistance and regulated MYCNOS expression by bioinformation analysis and experiment. MYCNOS has been reported to function as an antisense RNA of MYCN. MYCN was further found to affect SCLC chemoresistance through promoting expression of NOTCH pathway effectors HES1. Taken together, we suggest that MYCNOS-SE may be involved in chemoresistance of SCLC by recruiting FOXP1 and then regulating MYCNOS/MYCN/HES1 signaling. In this project, we intend to use the model of SCLC resistant cells (H69AR and H446DDP) and SCLC tissues to further confirm the role of MYCNOS-SE in SCLC chemoresistance. We also identify the mechanism of MYCNOS-SE in SCLC chemoresistance using ChIP-PCR, luciferase reporter assay, etc. Through the project, we will provide the scientific evidence to elucidate the molecular mechanism of SCLC chemoresistance.