Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer

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.

KEYWORDS:

• Cancer
• DNA methylation
• enhancer
• inflammation
• pentraxin-3

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Nadia Corrado for help with PAT-ChIP assays.

Funding

This work was supported by the European Commission (ERC to AM project PHII-669415; FP7-HEALTH-2011-ADITEC-N°280873 to AM; PK and RP were supported by ERC Advanced Grant to Gianluigi Condorelli CardioEpigen-294609); Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) (project FIRB RBAP11H2R9; project PRIN 2015YYKPNN); the Italian Ministry of Health (RF-2013-02355470 to CG); and Associazione Italiana Ricerca sul Cancro (AIRC and AIRC 5 × 1000).

Author contributions

M.R. designed and performed most experiments, analyzed the data, and drafted the manuscript; C.M.G. and F.P. performed some experiments; P.K. and S.S. performed bioinformatics studies and analyzed data; G.B., M.R., and L.L. provided human samples; A.M. critically revised the manuscript; R.P. and C.G. conceived the study, directed research, designed experiments, analyzed data, and wrote the manuscript.