Enzymatic TET-1 inhibition highlights different epigenetic behaviours of IL-1β and TNFα in tumour progression of OS cell lines

Abstract

Osteosarcoma (OS) is the most frequent primary malignant bone tumour, whose heterogeneity represents a major challenge for common antitumour therapies. Inflammatory cytokines are known to be necessary for OS progression. Therefore, to optimise therapy, it is important to discover reliable biomarkers by identifying the mechanism generating OS and investigating the inflammatory pathways that support the undifferentiated state. In this work, we highlight the differences of epigenetic activities of IL-1 beta and TNF alpha, and the susceptibility of TET-1 enzymatic inhibition, in tumour progression of three different OS cell lines. Investigating DNA methylation of IL-6 promoter and determining its expression, we found that TET enzymatic inhibition influences proliferation induced by inflammatory cytokines in OS cell lines. Moreover, Bobcat 339 treatment blocks IL-1 beta epigenetic action on IL-6 promoter, while only partially those of TNF alpha as well as inhibits IL-1 beta-dependent epithelial-mesenchymal transition (EMT) process, but only partially those of TNF alpha. In conclusion, this work highlights that IL-1 beta and TNF alpha have different effects on DNA demethylation in OS cell lines, making DNA methylation a potential biomarker of disease. Specifically, in IL-1 beta treatment, TET-1 inhibition completely blocks tumour progression, while in TNF alpha actions, it is only partially effective. Given that these two inflammatory pathways can be therapeutic targets for treating these tumours, knowledge of their distinct epigenetic behaviours can be useful for developing precise and specific therapeutic strategies for this disease.