SOX30在肺腺癌和肺鳞癌形成不同选择剪切蛋白的特异性定位、作用和机制研究

阐明肺癌机制是开展精准治疗和提高疗效的重要前提。选择剪接是肿瘤形成和异质的决定因素，也是鉴定和寻找更好肿瘤诊断、预后和治疗靶标的源泉，但机制不清楚。课题组前期发现，新抑癌基因SOX30在肺腺癌和肺鳞癌存在不同选择剪切，且与其表达定位和作用密切关联。进一步分析发现，SOX30形成不同选择剪切可能与特定H3k36me3有关；表达定位差异也可能与核定位信号（NLS）乙酰化相关。据此推测：不同H3k36me3招募特定结合蛋白及剪切因子形成不同SOX30选择剪切，并通过影响NLS乙酰化修饰决定SOX30表达分布和发挥作用。为此，本项目拟开展以下研究：①解析H3k36me3通过招募特定结合蛋白和剪切因子形成不同SOX30剪切的分子机制；②明确NLS乙酰化造成不同表达定位和功能的具体原因及机制；③确定H3k36me3修饰与NLS乙酰化修饰的关系。本研究将为肺癌精准治疗提供新途径，具有重要临床应用价值。

Elucidating the mechanism of lung cancer is an important prerequisite for developing precise treatment and improvement of curative effect. Alternative splicing is a common event，and is a source of biological complexity and diversity in vertebrates. Abnormal alternative splicing is an important cause of tumorigenesis and tumor heterogeneity, and is also the source of identifying and finding the better targets for tumor diagnosis, prognosis and treatment, while the mechanism is not clear. Our previous study has shown that the new tumor suppressor gene SOX30 had different alternative splicing in lung adenocarcinoma and squamous cell carcinoma, which was closely associated with its location and function. Further analyses revealed that the different alternative splicing of SOX30 might be related to specific H3k36me3, and the expression localization of SOX30 might also be associated with nuclear localization signal (NLS) acetylation. It was concluded that different H3k36me3 could recruit different binding proteins and splicing factors to form specific alternative splicing of SOX30, and determined the expression distribution and function of SOX30 through the influence of NLS acetylation modification. Therefore, the following studies will be carried out in this project: ① To analyze the molecular mechanism of H3k36me3 recruiting specific binding proteins and splicing factors to form different alternative splicing of SOX30; ② To clarify the specific reasons and mechanisms of different expression localization of SOX30 due to acetylation in NLS; ③ To determine the relationship between the H3k36me3 modification and the acetylation in NLS. This study will provide new methods for the precise treatment of lung cancer, with important clinical application value.