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.

PTEN的核定位对于其抑癌作用至关重要，在许多类型的癌症中，核PTEN的丢失比胞质PTEN更突出。但是，很少报道PTEN核特异性调节机制。基于发现核PTEN比胞质PTEN更不稳定的发现，我们在这里确定仅F-box蛋白22（FBXO22）诱导核素的泛素化，而不诱导赖氨酸221的胞质PTEN泛素化，这是核PTEN降解的原因。FBXO22通过泛素化和降解核PTEN发挥促进肿瘤的作用。因此，FBXO22在各种癌症类型中过表达，并有助于大肠癌组织中核PTEN的下调。累积而言，我们的研究报告了专门调节核PTEN稳定性的机制，