Abstract 1655: The ubiquitin protease UBP43 is a target for lung cancer therapy and prevention
Authors: Guo Yongli , Chinyengetere Fadzai , Dolinko Andrey V. , Lopez-Aguiar Alexandra , Galimberti Fabrizio , Ma Tian , Feng Qing , Andrew Angeline S. , Sekula David , Freemantle Sarah , Memoli Vincent , Dmitrovsky Ethan 
Published: June 2012

Abstract
Lung cancer is the leading cause of cancer mortality for women and men in the United States. Given this, there is a need to find new targets to combat lung cancer. This study explores the E1-like ubiquitin-activating enzyme (UBE1L) that associates with the interferon-stimulated gene 15 (ISG15), which complexes with cyclin D1 and other specific proteins. The ubiquitin protease UBP43 removes ISG15 from conjugated proteins. The UBE1L-ISG15-UBP43 pathway was previously proposed to inhibit lung carcinogenesis by repressing cyclin D1 expression. Our prior work is extended here by reporting that UBP43 is enzymatically active in cells. Also, gain of UBP43 expression specifically stabilizes cyclin D1 while UBP43 knock-down destabilizes cyclin D1, but not cyclin E or other D-type cyclins. This occurs by regulating ISG15 complexes with cyclin D1. UBP43 effects on cyclin D1 were not antagonized by cycloheximide treatment. Whether the deconjugase UBP43 was a lung cancer target was independently addressed through engineered gain and loss of UBP43 expression in lung cancer cells. UBP43 knock-down triggered apoptosis in these cells. In contrast, UBP43 over-expression promoted lung cancer cell growth by inhibiting apoptosis. That cyclin D1 plays a key role in conferring these effects was shown by engineered loss of UBP43 along with forced cyclin D1 expression. Cyclin D1 antagonized effects of loss of UBP43. Engineered UBP43 knock-down in lung cancer cells significantly increased apoptosis (P &lt; 0.05), reduced growth (P &lt; 0.05) and inhibited lung cancer formation (P &lt; 0.05) in FVB mice injected via tail veins with syngeneic lung cancer cells. In marked contrast, forced UBP43 over-expression in lung cancer cells antagonized the effects of interferon, cisplatin and all-trans-retinoic acid, indicating that UBP43 can regulate response to anti-neoplastic agents. To ascertain the clinical impact of this pathway, a paired normal-malignant human lung tissue array from 74 cases was examined for immunohistochemical expression profiles of UBP43 and cyclin D1 proteins. Notably, UBP43 was significantly increased in the malignant as compared to the adjacent normal lung tissues (P = 0.04 for adenocarcinoma and P = 0.02 for squamous cell carcinoma). Intriguingly, a direct relationship was found between UBP43 and cyclin D1, validating clinical relevance. Thus, UBP43 knock-down appears to exert its anti-neoplastic effects by destabilizing cyclin D1. Taken together, these findings establish that the deconjugase UBP43 is a tractable target for lung cancer therapy and prevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1655. doi:10.1158/1538-7445.AM2011-1655