Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer. (3rd July 2017)

• Record Type: Journal Article
• Authors: Rubino, Marcello; Kunderfranco, Paolo; Basso, Gianluca; Greco, Carolina Magdalen; Pasqualini, Fabio; Serio, Simone; Roncalli, Massimo; Laghi, Luigi; Mantovani, Alberto; Papait, Roberto; Garlanda, Cecilia
• Is Part Of: Oncoimmunology. Volume 6:Number 7(2017)
• Publication Date: 2017-07-03
• Subjects: Cancer -- DNA methylation -- enhancer -- inflammation -- pentraxin-3; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2017.1333215
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: PTX3 is a component of the humoral arm of innate immunity and an extrinsic oncosuppressor gene taming tumor-promoting inflammation. Here, we show that two enhancers differently regulate PTX3 expression: enhancer 1, located 230 kb upstream of PTX3 promoter, mediated the action of inflammatory transcription factors; and enhancer 2, encompassing PTX3 second exon, was implicated in pre-initiation complex assembly. Polycomb repressive complex 2 silenced these regulatory elements and the promoter in basal condition. Enhancer 1 was epigenetically inactivated in early colorectal cancer (CRC) stages, while the promoter and enhancer 2 showed increasingly DNA methylation during CRC progression from adenomas to stage II and III CRC. Inhibition of DNA methylation rescued PTX3 expression in CRC. Finally, enhancer 1 acquired the binding of STAT3 in stage I CRC, and inhibition of STAT3 phosphorylation restored PTX3 activity and decreased enhancer 1 methylation. Thus, the expression of PTX3 is under the control of two enhancers, which emerge as important fine regulators of PTX3 expression in inflammation and cancer.