PURPOSE: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). EXPERIMENTAL DESIGN: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. RESULTS: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. CONCLUSIONS: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.
PURPOSE: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of humancancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). EXPERIMENTAL DESIGN: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. RESULTS:EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. CONCLUSIONS: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.
Authors: Erick Riquelme; Milind Suraokar; Carmen Behrens; Heather Y Lin; Luc Girard; Monique B Nilsson; George Simon; Jing Wang; Kevin R Coombes; J Jack Lee; Waun Ki Hong; John Heymach; John D Minna; Ignacio I Wistuba Journal: Clin Cancer Res Date: 2014-05-21 Impact factor: 12.531
Authors: Pooja Hingorani; Edoardo Missiaglia; Janet Shipley; James R Anderson; Timothy J Triche; Mauro Delorenzi; Julie Gastier-Foster; Michele Wing; Douglas S Hawkins; Stephen X Skapek Journal: Clin Cancer Res Date: 2015-10-15 Impact factor: 12.531
Authors: Amir Avan; Francesco Crea; Elisa Paolicchi; Niccola Funel; Elena Galvani; Victor E Marquez; Richard J Honeywell; Romano Danesi; Godefridus J Peters; Elisa Giovannetti Journal: Mol Cancer Ther Date: 2012-05-23 Impact factor: 6.261
Authors: Yin P Hung; Fei Dong; Matthew Torre; Christopher P Crum; Raphael Bueno; Lucian R Chirieac Journal: Mod Pathol Date: 2020-06-05 Impact factor: 7.842
Authors: Cody J Peer; Mahadev Rao; Shawn D Spencer; Shandiz Shahbazi; Patricia S Steeg; David S Schrump; William D Figg Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2013-01-09 Impact factor: 3.205