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, Oct 09, 2015
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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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    ABSTRACT: The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.
    Open Biology 02/2014; 4(2):130217. DOI:10.1098/rsob.130217 · 5.78 Impact Factor
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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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    ABSTRACT: Although radiotherapy represents one of the most effective treatment modalities for patients with cancer, inherent and/or acquired resistance of cancer cells to radiotherapy is often an impediment to effective treatment. Diverse strategies have been developed to improve the efficacy of radiotherapy. The ubiquitin-proteasome system (UPS) operates in numerous vital biologic processes by controlling the protein turnover in cells. Ubiquitination is central to the UPS pathway, and it relies on the E3 ubiquitin ligases to catalyze the covalent attachment of ubiquitin to its protein substrates. Cullin-based RING ligases (CRLs) are the largest family of E3 ligases that are responsible for the ubiquitination and destruction of numerous cancer-relevant proteins. Its deregulation has been linked to many human cancers, making it an attractive target for therapeutic intervention. This review discusses how targeting the ubiquitin-proteasome system, particularly CRLs, is an exciting new strategy for radiosensitization in cancer and, specifically, focuses on MLN4924, a recently discovered small-molecule inhibitor of the NEDD8-activating enzyme, which is being characterized as a novel radiosensitizing agent against cancer cells by inactivating CRL E3 ubiquitin ligases.
    Translational oncology 10/2012; 5(5):305-12. DOI:10.1593/tlo.12229 · 2.88 Impact Factor
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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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    ABSTRACT: The cullin 4-RING ubiquitin ligase (CRL4) family employs multiple DDB1-CUL4 associated factors substrate receptors to direct the degradation of proteins involved in a wide spectrum of cellular functions. Aberrant expression of the cullin 4A (CUL4A) gene is found in many tumor types, while mutations of the cullin 4B (CUL4B) gene are causally associated with human X-linked mental retardation. This focused review will summarize our current knowledge of the two CUL4 family members in the pathogenesis of human malignancy and neuronal disease, and discuss their potential as new targets for cancer prevention and therapeutic intervention.
    Frontiers in Oncology 03/2012; 2:21. DOI:10.3389/fonc.2012.00021
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