Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, State Key Laboratory of Oncogenes and Related Genes and Chinese Academy of Medical Sciences Research Unit (NO.2019RU043), Shanghai Cancer Institute, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200025, Shanghai, China.
Nat Commun. 2020 Apr 6;11(1):1720. doi: 10.1038/s41467-020-15578-1.
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 的核定位对于其肿瘤抑制作用至关重要，在许多癌症中，核 PTEN 的丢失比细胞质 PTEN 更为突出。然而，核 PTEN 特异性的调节机制很少有报道。基于核 PTEN 比细胞质 PTEN 更不稳定的发现，我们在这里确定 F-box 仅蛋白 22（FBXO22）在赖氨酸 221 处诱导核而非细胞质 PTEN 的泛素化，这负责核 PTEN 的降解。FBXO22 通过泛素化和降解核 PTEN 发挥促进肿瘤的作用。相应地，FBXO22 在各种癌症类型中过表达，并有助于结直肠癌组织中核 PTEN 的下调。总之，我们的研究报告了专门调节核 PTEN 稳定性的机制，这为开发旨在完全重新激活作为肿瘤抑制因子的 PTEN 的治疗策略提供了机会。
