The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China.
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
Int J Mol Sci. 2022 Feb 4;23(3):1788. doi: 10.3390/ijms23031788.
Cytoplasmic chromatin fragments (CCF) are recognized by the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS), which activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway and promotes the production of inflammatory factors and breast cancer metastasis. However, the mechanisms by which CCF are formed in tumor cells and CCF activation cGAS promotes breast cancer metastasis remain unclear. Here, we report that the enhancer of zeste homolog 2 (EZH2) can promote the formation of CCF and activate the cGAS-STING pathway to promote breast cancer metastasis. Further research found that the EZH2-mediated CCF formation depended on high mobility group A1 (HMGA1), while the stability of EZH2 required ubiquitin-specific peptidase 7 (USP7), indicating that the EZH2-HMGA1-USP7 complex regulated CCF formation. Moreover, EZH2 can activate cGAS through CCF, requiring USP7 to deubiquitinate cGAS and stabilize cGAS. In vivo experimental results showed that EZH2 could promote breast cancer metastasis through CCF. Our findings highlight a new target for breast cancer metastasis. Targeting the EZH2-CCF-cGAS axis may be a potential therapeutic strategy for inhibiting breast cancer metastasis.
细胞质染色质片段 (CCF) 被细胞质 DNA 传感器环鸟苷酸-腺苷酸合酶 (cGAS) 识别，cGAS 激活 cGAS-STING（环鸟苷酸-腺苷酸合酶刺激干扰素基因）途径，促进炎症因子的产生和乳腺癌转移。然而，肿瘤细胞中 CCF 的形成机制以及 CCF 激活 cGAS 促进乳腺癌转移的机制尚不清楚。在这里，我们报告增强子结合蛋白 2 (EZH2) 可以促进 CCF 的形成并激活 cGAS-STING 途径，从而促进乳腺癌转移。进一步的研究发现，EZH2 介导的 CCF 形成依赖于高迁移率族蛋白 A1 (HMGA1)，而 EZH2 的稳定性需要泛素特异性肽酶 7 (USP7)，表明 EZH2-HMGA1-USP7 复合物调节 CCF 的形成。此外，EZH2 可以通过 CCF 激活 cGAS，需要 USP7 去泛素化 cGAS 并稳定 cGAS。体内实验结果表明，EZH2 可以通过 CCF 促进乳腺癌转移。我们的研究结果强调了乳腺癌转移的一个新靶点。靶向 EZH2-CCF-cGAS 轴可能是抑制乳腺癌转移的一种潜在治疗策略。
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