Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial−mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.

转移是癌症死亡的主要原因。循环肿瘤细胞 (CTC) 水平升高，即已侵入循环系统的转移性癌细胞，尤其与远处器官的定植和预后不良有关。然而，肿瘤细胞传播和定植所需的关键因素仍然难以捉摸。我们发现桥粒介导的细胞间粘附复合物的一种成分桥粒芯核蛋白 2 (DSG2) 的高表达促进了肿瘤的生长，增加了 CTC 簇的患病率，并促进了远处器官的定植。缺氧对DSG2的动态调节是这一过程的关键，因为原发性肿瘤缺氧区域DSG2的下调导致上皮-间质转化（EMT）基因表达升高，允许细胞从原发性肿瘤上脱离并进行血管内渗透。随后在血管内渗入和释放缺氧应激后对 DSG2 的抑制与在远处器官定殖的能力增加有关。DSG2 的这种动态调节是由缺氧诱导因子 1α (HIF1α) 介导的。与其更广泛观察到的促进缺氧诱导基因表达的功能相反，HIF1α 通过将多梳抑制复合物 2 组分 EZH2 和 SUZ12 募集到缺氧细胞中的 DSG2 启动子来抑制 DSG2。与我们的实验数据一致，DSG2 表达水平与乳腺癌患者的不良预后和复发风险相关。总之，这些结果证明了 DSG2 表达在转移中的重要性，并揭示了缺氧驱动转移的机制。随后在血管内渗入和释放缺氧应激后对 DSG2 的抑制与在远处器官定殖的能力增加有关。DSG2 的这种动态调节是由缺氧诱导因子 1α (HIF1α) 介导的。与其更广泛观察到的促进缺氧诱导基因表达的功能相反，HIF1α 通过将多梳抑制复合物 2 组分 EZH2 和 SUZ12 募集到缺氧细胞中的 DSG2 启动子来抑制 DSG2。与我们的实验数据一致，DSG2 表达水平与乳腺癌患者的不良预后和复发风险相关。总之，这些结果证明了 DSG2 表达在转移中的重要性，并揭示了缺氧驱动转移的机制。随后在血管内渗入和释放缺氧应激后对 DSG2 的抑制与在远处器官定殖的能力增加有关。DSG2 的这种动态调节是由缺氧诱导因子 1α (HIF1α) 介导的。与其更广泛观察到的促进缺氧诱导基因表达的功能相反，HIF1α 通过将多梳抑制复合物 2 组分 EZH2 和 SUZ12 募集到缺氧细胞中的 DSG2 启动子来抑制 DSG2。与我们的实验数据一致，DSG2 表达水平与乳腺癌患者的不良预后和复发风险相关。总之，这些结果证明了 DSG2 表达在转移中的重要性，并揭示了缺氧驱动转移的机制。