Cul4A is an oncogene in malignant pleural mesothelioma.
Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.
Hung
Ming-Szu
MS
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
Mao
Jian-Hua
JH
Xu
Zhidong
Z
Yang
Cheng-Ta
CT
Yu
Jau-Song
JS
Harvard
Chansonette
C
Lin
Yu-Ching
YC
Bravo
Dawn Therese
DT
Jablons
David M
DM
You
Liang
L
D002453:Cell Cycle; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008654:Mesothelioma / Q000235:genetics*; D009857:Oncogenes; D010997:Pleural Neoplasms / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C114234:CUL4A protein, human; D044842:Cullin Proteins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; C413374:p27 antigen; D020741:rho GTP-Binding Proteins