Trim21泛素化snail调控乳腺癌细胞EMT的表观遗传机制

Breast cancer is the most common invasive cancer in females worldwide. The Snail of transcription factors are core inducers of epithelial-to- mesenchymal transition (EMT). The regulatory factors of Snail play an important role in the study of breast cancer metastasis and treatment. In this project, we propose to identify the association and binding domain between TRIM21 and Snail, investigate that TRIM21 promotes ubiquitin-mediated degradation of Snail, reveal that TRIM21 regulates the EMT related genes and invasion and metastasis in breast cancer cells, finally demonstrates the epigenetic mechanism that TRIM21 ubiquitinates Snail to regulate EMT in breast cancer cells. Our study will not only reveal the epigenetic mechanism under breast cancer invasion and metastasis, but also facilitate the discovery of novel drug targets to treat breast cancer.

乳腺癌是女性发病率最高的恶性肿瘤，Snail作为EMT的核心诱导因子，研究其调控因子对明确乳腺癌转移及治疗至关重要。本项目拟通过E3泛素连接酶TRIM21和Snail相互作用及结合结构域的研究，明确TRIM21对Snail的泛素化及降解，揭示TRIM21对EMT相关基因及乳腺癌细胞侵袭与转移的调控，阐明Trim21泛素化snail调控乳腺癌细胞EMT的表观遗传机制，从而为明确乳腺癌的侵袭与转移提供理论依据，为乳腺癌的治疗提供新的靶向基因。

乳腺癌是女性发病率最高的恶性肿瘤，对乳腺癌侵袭转移机制及药物靶点的研究已成为生物学、临床医学的热点。因此，探究乳腺癌细胞中上皮间质细胞转移（EMT）发生与调控机制对于寻找乳腺癌侵袭与转移的靶基因以及发现新的治疗方法具有重要的意义。转录因子Snail是EMT的核心诱导物，但EMT的调控机制极为复杂，目前尙不十分明确。上皮细胞标示物E-cadherin表达被Snail直接抑制是经典的EMT转录调控机制。无论是在正常发育还是恶性肿瘤发展过程中，Snail-E-cadherin轴线都深刻地影响着上皮细胞增殖与可塑性。本研究表明MCF7、T47D乳腺癌细胞中，E3泛素连接酶TRIM21能够识别Snail，并通过B-Box结构域与Snail相互结合，进而发挥其泛素连接酶特性，通过泛素-蛋白酶体系统泛素化并降解Snail，从而经由Snail-E-cadherin轴线调控EMT，为阐明乳腺癌侵袭与转移机制提供理论依据，并为乳腺癌治疗药物开发提供新的靶向基因。