The \u03b2-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

Jie Xu,Xiufang Xiong,Yi Sun,Hua Li,Weihua Zhou,Guoan Chen,Yongchao Zhao,Pengyuan Liu,Mingjia Tan,Haomin Li,Fei Yang

doi:10.1038/ncomms14002

Abstract

β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation.

Highlights

Lung cancer, including small cell lung cancer and non-small cell lung cancer (NSCLC), is the leading cause of cancer-related death in the USA and around the world[1]
We found that in contrast to oncogenic b-TrCP1 and SKP2, FBXW2 acts as a tumour suppressor to inhibit growth and survival of lung cancer cells, and high FBXW2 expression predicts a better patient survival
To further determine whether FBXW2 is a substrate of SCF E3, we treated lung cancer A549 cells with MLN4924, a small molecule inhibitor of NEDD8-activating enzyme, which inactivates SCF E3 by inhibiting cullin-1 neddylation[51], and found MLN4924 causes a dose-dependent accumulation of FBXW2 (Supplementary Fig. 1b)

Summary

Introduction

Lung cancer, including small cell lung cancer and non-small cell lung cancer (NSCLC), is the leading cause of cancer-related death in the USA and around the world[1]. Like b-TrCP1, SKP2, another well-characterized F-box protein, acts as a classic oncogene which promotes proliferation and survival of cancer cells, mainly through targeted degradation of a number of tumour suppressive proteins, including p21 FBXW7, on the other hand, is a well-established tumour suppressor that targets various oncogenic proteins for degradation[45] Except for these three well-known F-box proteins, potential roles of remaining 66 F-box proteins in cancers, in lung cancer, are poorly understood, some of them are involved in normal physiology and disorders in the lung such as inflammatory lung disease[46]. Our study established a previously unknown signalling cascade of the b-TrCP-FBXW2SKP2 by forming the oncogene (b-TrCP)-tumour suppressor gene (FBXW2)-oncogene (SKP2) axis that regulates growth and survival of lung cancer cells via targeting each other for degradation

Methods

Results

Conclusion