KAT6A依赖的乙酰化SMAD3调控乳腺癌转移的分子机制

乳腺癌转移是当前临床治疗的难点，而SMAD3是调控乳腺癌转移的关键分子，但对其调控机制还不清楚。申请人在前期研究组蛋白乙酰转移酶KAT6A参与调控胶质瘤恶性增殖（Nat Commun 2017，Cancer Res 2017）时，利用质谱分析发现在乳腺癌中，KAT6A可以乙酰化非组蛋白SMAD3的K20/117位点，进一步发现SMAD3乙酰化可能通过调节免疫细胞因子的表达，激活肿瘤微环境的MDSC(骨髓来源的抑制性细胞)，抑制免疫，从而促进乳腺癌转移。本项目拟在前期研究的基础上，利用临床标本数据库、原位乳腺癌成瘤模型、RNA-Seq等方法，深入揭示KAT6A依赖的乙酰化SMAD3调控乳腺癌转移的分子机制；同时，探讨靶向KAT6A的小分子抑制剂单或联合PD-L1免疫治疗对乳腺癌转移的影响，从而揭示调控乳腺癌转移的新机制，促进发现临床检测肿瘤转移的新靶点和新治疗策略。

Breast cancer metastasis is relatively hard to treat in clinic, and SMAD3 is a key molecular to regulate breast cancer metastasis. However, the mechanism by which SMAD3 regulates metastasis is still unclear. The applicant previously demonstrated that KAT6A modulates glioma tumorigenesis (Nat Commun 2017，Cancer Res 2017). Recently, the applicant found that KAT6A acetylated non-histone protein SMAD3, and K20/117 acetylation of SMAD3 promoted activation of MDSCs (Myeloid-derived suppressor cells), leading to immun inhibition and tumor metastasis. In this project, the applicant will use clinical breast cancer datasets, orthotopic xenograft breast tumorigenesis, RNA-Seq, et al., and explore the mechanisms by which KAT6A-dependent acetylation of SMAD3 modulates breast cancer metastasis. The applicant will also explore the therapies of KAT6A inhibitor in combination with PD-L1 antibody in breast cancer metastasis. This will help not only to understand the molecular mechanisms of breast cancer metastasis, but also to provide new potential targets for clinical therapy.