Cul4A is an oncogene in malignant pleural mesothelioma

Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 11/2009; 15(2):350-8. DOI: 10.1111/j.1582-4934.2009.00971.x
Source: PubMed


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.

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Available from: Yu-Ching Lin
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    • "CUL4A has been found to be amplified in squamous cell carcinoma [95], adrenocortical carcinomas [96] and childhood medulloblastoma [97]. Its amplification and overexpression was also found in hepatocellular carcinomas [8], primary malignant pleural mesotheliomas [98], primary human breast cancers [2] and prostate cancers [99]. A recent study also observed overexpression of CUL4 in epithelial ovarian tumours especially in the invasive carcinoma specimens [100]. "
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    • "The cullins are a family of eight members, which do not have intrinsic catalytic activity, when acting alone, but instead are molecular scaffolds that facilitate the assembly of modular CRL complexes and mediate the transfer of ubiquitin from the E2-conjugating enzyme to the substrate proteins [22]. Cullin 1 is overexpressed in 40% of lung cancers [84], whereas cullin 4A expression is elevated in multiple cancer types, such as breast [85] [86] [87], hepatocellular [88], and mesothelioma [89]. Overexpression of cullin 4A in MCF10A cells abrogated the G2/M cell cycle checkpoint in response to radiation-induced DNA damage [90]. "
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    • "Genome-wide analysis of human cancers revealed CUL4A amplification in 5% of familial and sporadic breast cancers, and as high as 20% in the basal-like breast cancer subtype that is associated with aggressive growth and poor prognosis (Melchor et al., 2009). CUL4A amplification has also been found in squamous cell carcinomas (Shinomiya et al., 1999), adrenocortical carcinomas (Dohna et al., 2000), childhood medulloblastoma (Michiels et al., 2002), hepatocellular carcinomas (Yasui et al., 2002), and primary malignant pleural mesotheliomas (Hung et al., 2011). Recently, genome-wide high-density SNP arrays further revealed high CUL4A gene copy number in a subset of lung and ovarian carcinomas, as well as other solid tumor types (Beroukhim et al., 2010). "
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