PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression
PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression
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DOI：
10.1038/s41467-019-08481-x
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发表时间：
2019-02-07
影响因子：
16.6
通讯作者：
Song, Min Sup
中科院分区：
文献类型：
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作者：
Park, Mi Kyung;Yao, Yixin;Song, Min Sup
PTEN是一种脂质磷酸酶，能拮抗PI3K/AKT通路，被认为是一种主要的剂量依赖性肿瘤抑制因子。因此，控制PTEN水平的细胞机制提供了潜在的治疗途径，但这些途径尚不清楚。在这里，我们证明了PTEN通过PI3K/FOXO途径转录上调去泛素酶USP11而在调节自身稳定性方面发挥了意想不到的作用，并进一步表明这种前馈机制与其肿瘤抑制作用有关，因为缺乏USP11的小鼠对依赖PTEN的肿瘤的起始、生长和转移表现出更高的敏感性。值得注意的是，USP11在癌症患者中表达下调，并与PTEN表达和FOXO核定位相关。因此，我们的研究结果表明，PTEN-PI3K-FOXO-USP11构成了调节前馈回路，提高了PTEN的稳定性和抑瘤活性。
PTEN is a lipid phosphatase that antagonizes the PI3K/AKT pathway and is recognized as a major dose-dependent tumor suppressor. The cellular mechanisms that control PTEN levels therefore offer potential routes to therapy, but these are as yet poorly defined. Here we demonstrate that PTEN plays an unexpected role in regulating its own stability through the transcriptional upregulation of the deubiquitinase USP11 by the PI3K/FOXO pathway, and further show that this feedforward mechanism is implicated in its tumor-suppressive role, as mice lacking Usp11 display increased susceptibility to PTEN-dependent tumor initiation, growth and metastasis. Notably, USP11 is downregulated in cancer patients, and correlates with PTEN expression and FOXO nuclear localization. Our findings therefore demonstrate that PTEN-PI3K-FOXO-USP11 constitute the regulatory feedforward loop that improves the stability and tumor suppressive activity of PTEN.