β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer

Jia Ma; Yanwei Lu; Sheng Zhang; Yan Li; Jing Huang; Zhongyuan Yin; Jinghua Ren; Kai Huang; Li Liu; Kunyu Yang; Gang Wu; Shuangbing Xu

doi:10.1038/s41418-017-0055-6

β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer

Cell Death Differ. 2018 Aug;25(8):1473-1485. doi: 10.1038/s41418-017-0055-6. Epub 2018 Feb 2.

Authors

Jia Ma¹, Yanwei Lu¹, Sheng Zhang¹, Yan Li¹, Jing Huang¹, Zhongyuan Yin¹, Jinghua Ren¹, Kai Huang², Li Liu¹, Kunyu Yang¹, Gang Wu¹, Shuangbing Xu³

Affiliations

¹ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
² Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
³ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. xsb723@hust.edu.cn.

Abstract

Aberrant expression of FOXN2, a member of the Forkhead box transcription factors, has been found in several types of cancer. However, the underlying mechanisms of FOXN2 deregulation in tumorigenesis remain largely unknown. Here, we find that FOXN2 binds to and is ubiquitinated by β-Trcp ubiquitin ligase and RSK2 kinase for degradation. Furthermore, we demonstrate that the Ser365 and Ser369 sites in a conserved DSGYAS motif are critical for the degradation of FOXN2 by β-Trcp and RSK2. Moreover, gain-of-function and loss-of-function studies show that FOXN2 impairs cell proliferation in vitro and in vivo and enhances the radiosensitivity of lung cancer. Importantly, β-Trcp-mediated and RSK2-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer cells. Collectively, our study reveals a novel post-translational modification of FOXN2 and suggests that FOXN2 may be a potential therapeutic and radiosensitization target for lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Animals
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic*
Forkhead Transcription Factors / antagonists & inhibitors
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Binding
RNA Interference
RNA, Small Interfering / metabolism
RNA, Small Interfering / therapeutic use
Radiation Tolerance*
Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
Ribosomal Protein S6 Kinases, 90-kDa / genetics
Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
Sequence Alignment
Ubiquitination
beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

FOXN2 protein, human
Forkhead Transcription Factors
RNA, Small Interfering
beta-Transducin Repeat-Containing Proteins
Ribosomal Protein S6 Kinases, 90-kDa
ribosomal protein S6 kinase, 90kDa, polypeptide 3