E3 ubiquitin ligase Pirh2 enhances tumorigenic properties of human non-small cell lung carcinoma cells
Alexandra Daks1,*, Alexey Petukhov1,2,3,*, Olga Fedorova1, Oleg Shuvalov1, Valeriy Merkulov1, Elena Vasileva1, Alexey Antonov4, and Nikolai A. Barlev1
1 Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
2 Almazov Federal North-West Medical Research Centre, Institute of Hematology, St Petersburg, Russia
3 National Research University of Information Technologies, Mechanics and Optics, St Petersburg, Russia
4 MRC Toxicology Unit, Leicester, UK
* These authors made equal contribution
Correspondence:
Nikolai Barlev, email:
Correspondence:
Alexandra Daks, email:
Keywords: Pirh2, RCHY1, H1299, non-small cell lung cancer, drug resistance, EMT, xCELLigence
Received: October 07, 2016 Accepted: November 07, 2016 Published: November 09, 2016
Abstract
The product ofRCHY1 human gene, Pirh2, is a RING-finger containing E3 ligase that modifies p53 with ubiquitin residues resulting in its subsequent degradation in proteasomes. Transcription of RCHY1 is regulated by p53 itself thus forming a negative regulatory feedback loop. Functionally, by eliminating p53, Pirh2 facilitates tumorigenesis. However, the role of Pirh2 in cancer cells lacking p53 is yet not well understood. Therefore, we decided to elucidate the role of Pirh2 in p53-negative human non-small cell lung carcinoma cells, H1299. We found that ectopic expression of Pirh2 enhanced cell proliferation, resistance to doxorubicin, and increased migration potential. Ablation of Pirh2 by specific shRNA reversed these phenotypes. Mechanistically, Pirh2 increased mRNA and protein levels of the c-Myc oncogene. The bioinformatics data indicate that co-expression of both c-Myc and Pirh2 strongly correlated with poor survival of lung cancer patients. Collectively, our results suggest that Pirh2 can be considered as a potential pharmacological target for developing anticancer therapies to treat p53-negative cancers.
