The regulation of CPNE1 ubiquitination by the NEDD4L is involved in the pathogenesis of non-small cell lung cancer

Ruochen Zhang; Weijie Zhang; Yuanyuan Zeng; Yue Li; Jieqi Zhou; Yang Zhang; Anqi Wang; Yantian Lv; Jianjie Zhu; Zeyi Liu; Jian-An Huang

doi:10.1038/s41420-021-00736-1

The regulation of CPNE1 ubiquitination by the NEDD4L is involved in the pathogenesis of non-small cell lung cancer

Cell Death Discov. 2021 Nov 6;7(1):336. doi: 10.1038/s41420-021-00736-1.

Authors

Ruochen Zhang^#^{1

2}, Weijie Zhang^#^{1

2}, Yuanyuan Zeng^#^{1

2

3}, Yue Li^{1

2}, Jieqi Zhou^{1

2}, Yang Zhang^{1

2}, Anqi Wang^{1

2}, Yantian Lv^{1

2}, Jianjie Zhu^{1

2

3}, Zeyi Liu^{4

5

6}, Jian-An Huang^{7

8

9}

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
² Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
³ Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China.
⁴ Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China. liuzeyisuda@163.com.
⁵ Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China. liuzeyisuda@163.com.
⁶ Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China. liuzeyisuda@163.com.
⁷ Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China. huang_jian_an@163.com.
⁸ Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China. huang_jian_an@163.com.
⁹ Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China. huang_jian_an@163.com.

^# Contributed equally.

Abstract

Our previous studies revealed that oncogene CPNE1 is positively correlated with the occurrence, TNM stage, lymph node metastasis, and distant metastasis of non-small-cell lung cancer (NSCLC), and it could be regulated by micro RNAs. But no direct role of post-translational modification of CPNE1 in NSCLC has been reported. This study confirms that CPNE1 is degraded by two pathways: the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. CPNE1 binds with the ubiquitin molecule via its K157 residue. Moreover, we determined that the ubiquitin ligase NEDD4L can mediate the ubiquitination of CPNE1 and promote its degradation. In addition, we find that NEDD4L knockdown promotes the proliferation and metastasis of NSCLC cells by regulating CPNE1 in vitro and vivo. This study aims to further investigate the mechanism of CPNE1 ubiquitination in the occurrence and development of NSCLC and provide a new potential target for NSCLC treatment.