FBXO22 degrades nuclear PTEN to promote tumorigenesis
FBXO22 degrades nuclear PTEN to promote tumorigenesis
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FBXO22 降解核 PTEN 促进肿瘤发生
DOI：
10.1038/s41467-020-15578-1
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发表时间：
2020-04-06
影响因子：
16.6
通讯作者：
Shen, Shao-Ming
中科院分区：
文献类型：
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作者：
Ge, Meng-Kai;Zhang, Na;Shen, Shao-Ming
PTEN的核定位对于其肿瘤抑制作用是必需的，并且在许多种类的癌症中，核PTEN的丢失比胞质PTEN更突出。然而，核PTEN特异性调控机制很少报道。基于核PTEN比细胞质PTEN更不稳定的发现，在这里，我们鉴定了F-box only蛋白22（FBXO 22）诱导核而不是细胞质PTEN在赖氨酸221处的泛素化，这是核PTEN降解的原因。FBXO 22通过泛素化和降解核内的PTEN发挥促肿瘤作用。因此，FBXO 22在各种癌症类型中过表达，并有助于结直肠癌组织中的核PTEN下调。累积起来，我们的研究报告了特异性调节核PTEN稳定性的机制，这将为开发旨在实现PTEN作为肿瘤抑制因子的完全重新激活的治疗策略提供机会。
Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.