TRIM24调控mRNA可变剪切促进三阴型乳腺癌远端转移的机制研究

Breast cancer is a very hetergenous disease. The major cause of breast cancer death is metastasis. Triple negative breast cancer has poor prognosis and high metastasis rate. During metastasis，pre-mRNAs of many metastasis-related genes are alternatively spliced (AS) and previous studies have shown that this AS switch occurs at transcriptome level. However, it is still not clear how AS is regulated when triple negative breast cancer metastasizes. Our preliminary data demonstrates that TRIM24 interacts with multiple splicing factors and regulates AS of metastasis-realated genes in breast cancer cells. In agreement with this, TRIM24 is overpressed in breast cancer and its overexpression is associated with poor prognosis. Silencing TRIM24 in triple-negative breast cancer cells significantly decreased their capacity of migration and colony formation. Previous study has shown that TRIM24 is a chromatin reader recognizing H3K4me0 and H3K23ac. Therefore, we hypothesize that overexpressed TRIM24 in triple negative breast cancer cells regconizes H3K4me0 and H3K23ac, couples splicing factors with chromatin, regulates AS of metastasis-related genes, thus promotes cancer cell to metastasize.

乳腺癌是一种高度异质性的肿瘤，肿瘤的远端转移是患者死亡的主要原因。其中三阴型乳腺癌预后不佳，远端转移率较高。乳腺癌细胞发生远端转移时，大量转移相关基因的mRNA前体发生可变剪切切换，研究表明这一切换发生在转录组水平上。但是目前并不清楚可变剪切切换在三阴型乳腺癌远端转移过程中是如何被调控的。我们证实TRIM24可以与剪切体蛋白相结合，并可以调节乳腺癌细胞中转移相关基因的可变剪切。与此相对应，TRIM24过量表达的乳腺癌患者预后较差，在三阴型乳腺癌细胞中沉默TRIM24显著降低了细胞的集落形成和迁移能力。以往的研究证明TRIM24可以识别组蛋白修饰H3K4me0和H3K23ac。据此我们提出假说：乳腺癌患者中过量表达的TRIM24通过识别H3K4me0和H3K23ac，偶联剪切体蛋白与染色质，调控转移相关基因的mRNA可变剪切切换，促进肿瘤的转移。

三阴型乳腺癌（TNBC）缺乏有效靶点，治疗效果不嘉。TRIM24是组蛋白H3 23位赖氨酸乙酰化识别蛋白，在TNBC中表达增加，并与乳腺癌患者的预后密切相关，但是其作用机制不明。本研究发现ERα与PR负向调控TRIM24表达，揭示了TRIM24在TNBC中的表达调控机制。同时发现TRIM24与组蛋白H3 23位乙酰转移酶KAT6B协同调控MYC与SNAIL等基因的表达，促进多种乳腺癌细胞的增殖，为TNBC的治疗提供了新的靶点与潜在的治疗方案。同时我们发现TRIM24结合的剪切因子PRPF8促进非小细胞肺癌的增殖、转移与顺铂耐药，为非小细胞肺癌肺癌治疗提供了新的药物靶点。此外，我们还发现TRIM24结合的剪切蛋白SF3B3与乳腺癌预后密切相关，可以作为乳腺癌与预后的分子标记物。SF3B3通过调控EZH2和MCL1的可变剪切促进包括TNBC在内的多种亚型乳腺癌的增殖，并可以增强细胞对内分泌治疗的耐受。这一研究揭示了可变剪切在乳腺癌中作用于分子机制，为设计开发新的乳腺癌治疗药物提供了理论基础。