CircRREB1 promotes gastrointestinal cancer metastasis and MDSC-controlled immune evasion

It remains unclear whether super-enhancers (SEs) can drive expression of circular RNAs (circRNA) in gastrointestinal cancers (GI cancers). We first identified circRREB1 as a novel SE-driven circRNA in GI cancers and HNRNPL as the RNA binding protein controlling circRREB1 biogenesis. Indeed, SE-driven HNRNPL leads to high circRREB1 expression in GI cancers, which is regulated by transcription factor MAZ. circRREB1 could promote invasion and metastasis of cancer cells in vitro and in vivo. Mechanistically, circRREB1 binds to the SRSF3-XRN1-YTHDC2 complex in cytoplasm, destabilizes the m⁶A-modified CD44 mRNAs, and, thus, enhances metastasis of cancer cells. Consistently, high circRREB1 levels in malignant tissues are associated with poor patient prognosis. Although showing no impacts on tumor growth in nude mice, circRreb1 accelerates tumor proliferation in immunocompetent mice. Interestingly, circRreb1 elevates Ets1 expression through a competing endogenous RNA mechanism, up-regulates Cxcl2 expression and secretion, drives myeloid-derived suppressor cells (MDSCs) infiltration to tumors and contributes to formation of immunosuppressive tumor microenvironments. In line with this, depletion of MDSCs abrogates the oncogenic effects of circRreb1 in vivo. Notably, circRREB1 silencing synergizes with anti-PD1 therapy to activate antitumor immunity, offering novel insights into circRNA-mediated cancer epigenetics and promising therapeutic targets.