FBXO22 degrades nuclear PTEN to promote tumorigenesis

Meng-Kai Ge,Zhan-Ming Li,Cheng Zhang,Shao-Ming Shen,Jing Sun,Li Xia,Na Zhang,Shuang-Shu Dong,Yan Ji,Guo-Qiang Chen,Min-Hua Zheng

doi:10.1038/s41467-020-15578-1

Abstract

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.

Highlights

Nuclear localization of Phosphatase and tensin homolog on chromosome 10 (PTEN) is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers
We observed that only a small portion of transiently expressed C-terminal green fluorescent protein (GFP)-tagged PTEN (PTEN-GFP) in PTEN knockout human embryonic kidney 293T cells showed nuclear localization, which was dramatically increased in the presence of proteasome inhibitor MG132 (Fig. 1a)
As for this, 293T cells and mouse embryonic fibroblasts (MEF) were treated with proteasome inhibitors MG132 and Bortezomib (PS341), along with the lysosome inhibitor NH4Cl and the endoplasmic reticulum to Golgi transport inhibitor Brefeldin A (BFA), as PTEN had been reported to be degraded by Sirtuin 4 through lysosome pathway[40]

Summary

Introduction

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. PTEN has been reported to dephosphorylate itself and several other protein substrates to exert its tumor-suppressive functions[4,5,6,7,8]. PTEN is known to act as a scaffold protein to exert phosphataseindependent function, which is as significant as its lipid phosphatase activity to tumor suppression[9,10,11,12]. Like protein 1 (CDH1) to enhance its E3 ligase activity, resulting in the degradation of oncogenic substrates polo-like kinase 1 (PLK1), Aurora A and Cyclin A214. The expressions of these substrates are later used to evaluate the activity of nuclear PTEN15,16. Nuclear PTEN regulates alternative premRNA splicing events through its association with spliceosome[20] or arginine methylation[21]

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Results

Conclusion