Theranostics 2018; 8(13):3517-3529. doi:10.7150/thno.24401

Research Paper

HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

Dong Yang1,2*, Daomei Cheng3*, Qiu Tu1*, Huihui Yang1, Bin Sun1, Lanzhen Yan1,4, Hongjuan Dai1, Jierong Luo5, Bingyu Mao6, Yi Cao1, Xiaoping Yu3✉, Hua Jiang2✉, Xudong Zhao1,4,7,8✉

1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
2. Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, China.
3. Chengdu Medical College, Chengdu, Sichuan 610500, China.
4. Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
5. School of Mathematical Science, Zhejiang University, Zhejiang 310027, China.
6. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
7. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
8. KIZ-SU Joint laboratory of animal model and drug development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215000, China.
* Co-first authors

Abstract

Lung cancer is the most frequent cancer type and the leading cause of tumor-associated deaths worldwide. TP53 is an important tumor suppressor gene and is frequently inactivated in lung cancer. E3 ligases targeting p53, such as MDM2, are involved in the development of lung cancer. The E3 ligase HUWE1, which targets many tumor-associated proteins including p53, has been reported to be highly expressed in lung cancer; however, its role in lung tumorigenesis is unclear.

Methods: The expression of HUWE1 and p53 in lung cancer cells was modulated and the phenotypes were assessed by performing soft agar colony forming assays, cell cycle analysis, BrdU incorporation assays, and xenograft tumor growth assays. The effect on tumorigenesis in genetically-engineered mice was also analyzed. The mechanism through which HUWE1 sustained lung cancer cell malignancy was confirmed by western blotting. HUWE1 expression in clinical lung cancer was identified by immunohistochemistry and validated by analyzing lung adenocarcinoma and lung squamous carcinoma samples from the Cancer Genome Atlas (TCGA) database. Finally, we assessed the association between HUWE1 expression and patient outcome using online survival analysis software including survival information from the caBIG, GEO, and TCGA database.

Results: Inactivation of HUWE1 in a human lung cancer cell line inhibited proliferation, colony-forming capacity, and tumorigenicity. Mechanistically, this phenotype was driven by increased p53, which was due to attenuated proteasomal degradation by HUWE1. Up-regulation of p53 inhibited cancer cell malignancy, mainly through the induction of p21 expression and the down-regulation of HIF1α. Huwe1 deletion completely abolished the development of EGFRVIII-induced lung cancer in Huwe1 conditional knockout mice. Furthermore, survival analysis of lung cancer patients showed that increased HUWE1 expression is significantly associated with worse prognosis.

Conclusion: Our data suggest that HUWE1 plays a critical role in lung cancer and that the HUWE1-p53 axis might be a potential target for lung cancer therapy.

Keywords: HUWE1, p53, lung cancer, mouse model

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How to cite this article:
Yang D, Cheng D, Tu Q, Yang H, Sun B, Yan L, Dai H, Luo J, Mao B, Cao Y, Yu X, Jiang H, Zhao X. HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53. Theranostics 2018; 8(13):3517-3529. doi:10.7150/thno.24401. Available from http://www.thno.org/v08p3517.htm