FOXR2 is an epigenetically regulated pan-cancer oncogene that activates ETS transcriptional circuits

Abstract

Forkhead Box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly express FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for both FOXR2 expression as well as proliferation in FOXR2-expressing cancer cells. FOXR2 expression is sufficient to enhance tumor formation, and coopts ETS family transcriptional circuits across cancers. Taken together, this study identifies FOXR2 as potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of ETS transcriptional circuit hijacking by FOXR2 extends the mechanisms known to activate ETS transcription factors and highlights a mechanism through which transcription factor families cooperate to enhance tumorigenesis.