{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:45:36Z","timestamp":1778690736584,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Schweizerischer Nationalfonds zur F&amp;#x00F6;rderung der Wissenschaftlichen Forschung","award":["PP00P3_159269"],"award-info":[{"award-number":["PP00P3_159269"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 &lt; 0.5 \u00b5M). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S\/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.<\/jats:p>","DOI":"10.3390\/cancers12113460","type":"journal-article","created":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T09:46:18Z","timestamp":1605865578000},"page":"3460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"12","author":[{"given":"Mayura","family":"Meerang","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Kreienb\u00fchl","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Orlowski","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seraina L. C.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7444-9829","authenticated-orcid":false,"given":"Michaela B.","family":"Kirschner","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5900-9040","authenticated-orcid":false,"given":"Isabelle","family":"Opitz","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1200\/JCO.2003.11.136","article-title":"Phase iii study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma","volume":"21","author":"Vogelzang","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/bjc.1997.91","article-title":"Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma","volume":"75","author":"Bjorkqvist","year":"1997","journal-title":"Br. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1016\/j.febslet.2014.04.001","article-title":"Molecular insights into nf2\/merlin tumor suppressor function","volume":"588","author":"Cooper","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.tcb.2007.03.006","article-title":"Shedding light on merlin\u2019s wizardry","volume":"17","author":"Okada","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.cell.2010.01.029","article-title":"Merlin\/nf2 suppresses tumorigenesis by inhibiting the e3 ubiquitin ligase crl4(dcaf1) in the nucleus","volume":"140","author":"Li","year":"2010","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.molonc.2016.06.005","article-title":"Low merlin expression and high survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma","volume":"10","author":"Meerang","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1177\/1947601910382899","article-title":"Cullins and cancer","volume":"1","author":"Lee","year":"2010","journal-title":"Genes Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"130217","DOI":"10.1098\/rsob.130217","article-title":"Cul4a ubiquitin ligase: A promising drug target for cancer and other human diseases","volume":"4","author":"Sharma","year":"2014","journal-title":"Open Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/j.1582-4934.2009.00971.x","article-title":"Cul4a is an oncogene in malignant pleural mesothelioma","volume":"15","author":"Hung","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/path.4352","article-title":"Lung tumourigenesis in a conditional cul4a transgenic mouse model","volume":"233","author":"Yang","year":"2014","journal-title":"J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1007\/s12032-013-0534-7","article-title":"Cullin 4b is a novel prognostic marker that correlates with colon cancer progression and pathogenesis","volume":"30","author":"Jiang","year":"2013","journal-title":"Med. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15209","DOI":"10.18632\/oncotarget.3829","article-title":"Accelerated hepatocellular carcinoma development in cul4b transgenic mice","volume":"6","author":"Yuan","year":"2015","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/embor.2008.183","article-title":"Function and regulation of protein neddylation. \u2019Protein modifications: Beyond the usual suspects\u2019 review series","volume":"9","author":"Rabut","year":"2008","journal-title":"EMBO Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.molcel.2009.12.024","article-title":"Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: The nedd8 e1 inhibitor mln4924 forms a nedd8-amp mimetic in situ","volume":"37","author":"Brownell","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1517\/13543784.2012.707192","article-title":"Mln4924: A novel first-in-class inhibitor of nedd8-activating enzyme for cancer therapy","volume":"21","author":"Nawrocki","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"Gepia: A web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1757","DOI":"10.1038\/cddis.2015.124","article-title":"Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual pi3k\/mtor inhibitors","volume":"6","author":"Echeverry","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1158\/0008-5472.CAN-10-2122","article-title":"Inhibition of nedd8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating cdt1 turnover","volume":"71","author":"Milhollen","year":"2011","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nature07884","article-title":"An inhibitor of nedd8-activating enzyme as a new approach to treat cancer","volume":"458","author":"Soucy","year":"2009","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5792","DOI":"10.1038\/s41388-019-0840-4","article-title":"Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via nf-kappab-ccl2 signaling in lung cancer","volume":"38","author":"Zhou","year":"2019","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.molcel.2011.05.033","article-title":"X-linked mental retardation gene cul4b targets ubiquitylation of h3k4 methyltransferase component wdr5 and regulates neuronal gene expression","volume":"43","author":"Nakagawa","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.ccr.2012.10.024","article-title":"Crl4b catalyzes h2ak119 monoubiquitination and coordinates with prc2 to promote tumorigenesis","volume":"22","author":"Hu","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.molcel.2012.09.004","article-title":"Ezh2 generates a methyl degron that is recognized by the dcaf1\/ddb1\/cul4 e3 ubiquitin ligase complex","volume":"48","author":"Lee","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative molecular characterization of malignant pleural mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.omtn.2017.12.010","article-title":"Microrna-300 regulates the ubiquitination of pten through the crl4b(dcaf13) e3 ligase in osteosarcoma cells","volume":"10","author":"Chen","year":"2018","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1080\/21691401.2019.1652623","article-title":"Circular rna zfr accelerates non-small cell lung cancer progression by acting as a mir-101-3p sponge to enhance cul4b expression","volume":"47","author":"Zhang","year":"2019","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.yexmp.2014.09.016","article-title":"Analysis of microrna expression signatures in malignant pleural mesothelioma, pleural inflammation, and atypical mesothelial hyperplasia reveals common predictive tumorigenesis-related targets","volume":"97","author":"Chavez","year":"2014","journal-title":"Exp. Mol. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s10637-016-0398-8","article-title":"Targeting the protein ubiquitination machinery in melanoma by the nedd8-activating enzyme inhibitor pevonedistat (mln4924)","volume":"35","author":"Wong","year":"2017","journal-title":"Investig. New Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1158\/1535-7163.MCT-16-0821","article-title":"Combined inhibition of nedd8-activating enzyme and mtor suppresses nf2 loss-driven tumorigenesis","volume":"16","author":"Cooper","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/S1097-2765(03)00099-6","article-title":"A p53-dependent checkpoint pathway prevents rereplication","volume":"11","author":"Vaziri","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.ccr.2013.02.013","article-title":"Macrophage regulation of tumor responses to anticancer therapies","volume":"23","author":"Lewis","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5234","DOI":"10.1002\/cncr.26143","article-title":"Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma","volume":"117","author":"Burt","year":"2011","journal-title":"Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.3389\/fonc.2019.01366","article-title":"The immune microenvironment in mesothelioma: Mechanisms of resistance to immunotherapy","volume":"9","author":"Chu","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.ajpath.2010.12.014","article-title":"Identification of novel markers for the diagnosis of malignant pleural mesothelioma","volume":"178","author":"Gueugnon","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kishimoto, T., Fujimoto, N., Ebara, T., Omori, T., Oguri, T., Niimi, A., Yokoyama, T., Kato, M., Usami, I., and Nishio, M. (2019). Serum levels of the chemokine ccl2 are elevated in malignant pleural mesothelioma patients. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6419-1"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4812","DOI":"10.4049\/jimmunol.1300089","article-title":"Ikappabzeta is a transcriptional key regulator of ccl2\/mcp-1","volume":"190","author":"Hildebrand","year":"2013","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.ejca.2010.09.044","article-title":"Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: An exploratory analysis","volume":"47","author":"Sidi","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nprot.2008.226","article-title":"Spheroid-based drug screen: Considerations and practical approach","volume":"4","author":"Friedrich","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1177\/1087057107306839","article-title":"A reliable tool to determine cell viability in complex 3-d culture: The acid phosphatase assay","volume":"12","author":"Friedrich","year":"2007","journal-title":"J. Biomol. Screen"},{"key":"ref_41","first-page":"319","article-title":"Body condition scoring: A rapid and accurate method for assessing health status in mice","volume":"49","author":"Foltz","year":"1999","journal-title":"Comp. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3460\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:34:57Z","timestamp":1760178897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cancers12113460"],"URL":"https:\/\/doi.org\/10.3390\/cancers12113460","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]}}}