A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness.
A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness.
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DOI：
10.18632/oncotarget.4236
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发表时间：
2015-08-07
期刊：
影响因子：
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通讯作者：
Manfioletti G
中科院分区：
文献类型：
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作者：
Pegoraro S;Ros G;Ciani Y;Sgarra R;Piazza S;Manfioletti G
高迁移率族A1（HMGA 1）是一种促进肿瘤转化和进展的结构染色质因子。然而，HMGA 1发挥其致癌功能的机制尚未完全了解。在这里，我们表明，细胞周期蛋白E2（CCNE 2）的行为下游的HMGA 1调节运动和基底样乳腺癌细胞的侵袭性，通过促进核定位和活动的雅普，下游调解人的河马途径。从机制上讲，Hippo途径的核心激酶MST 1/2和LATS 1/2的活性是HMGA 1和CCNE 2介导的雅普定位调节所需的。在乳腺癌患者中，高水平的HMGA 1和CCNE 2表达与雅普/TAZ特征相关，支持这种联系。此外，我们提供的证据表明，CDK抑制剂诱导雅普从细胞核到细胞质的易位，导致其活性降低。这些发现揭示了HMGA 1和Hippo通路之间的关联，该通路与干细胞生物学、组织稳态和癌症相关。
High Mobility Group A1 (HMGA1) is an architectural chromatin factor that promotes neoplastic transformation and progression. However, the mechanism by which HMGA1 exerts its oncogenic function is not fully understood. Here, we show that cyclin E2 (CCNE2) acts downstream of HMGA1 to regulate the motility and invasiveness of basal-like breast cancer cells by promoting the nuclear localization and activity of YAP, the downstream mediator of the Hippo pathway. Mechanistically, the activity of MST1/2 and LATS1/2, the core kinases of the Hippo pathway, are required for the HMGA1- and CCNE2-mediated regulation of YAP localization. In breast cancer patients, high levels of HMGA1 and CCNE2 expression are associated with the YAP/TAZ signature, supporting this connection. Moreover, we provide evidence that CDK inhibitors induce the translocation of YAP from the nucleus to the cytoplasm, resulting in a decrease in its activity. These findings reveal an association between HMGA1 and the Hippo pathway that is relevant to stem cell biology, tissue homeostasis, and cancer.