A tumor suppressive-molecular axis EP300/circRERE/miR-6837-3p/MAVS activates type I interferon pathway and anti-tumor immunity to suppress colorectal cancer
Purpose: The oncogenic role of circRNAs has been well-studied in cancers including colorectal cancer (CRC). However, tumor-suppressive circRNAs and the mechanism through which they exert their anti-tumor effects remain largely unknown. We aim to find out the critical tumor-suppressive circRNAs and their possibility to serve as gene therapy targets.  Experimental Design: CircRNA sequencing, gain- and loss- of function experiments,and transcriptomic analysis were performed to find tumor-suppressive and anti-tumor immunity effects of circRERE. Molecular biology experiments were conducted for mechanism exploration. Finally, we conducted adeno-associated virus to deliver circRERE (circRERE-AAV) and evaluated circRERE-AAV alone and in combination with anti-PD-1 antibody in C57BL/6J mice bearing subcutaneous MC38 tumors.  Results: CircRERE is lowly expressed in CRC and its lower expression predicts worse prognosis of CRC patients in clinic. Overexpression of circRERE inhibits the malignant behaviors of CRC in vitro and in vivo, while knockdown exhibits the opposite effects. The expression of circRERE is regulated by EP300, a histone acetyltransferase downregulated in CRC as well. Mechanistically, circRERE acts as a ceRNA to sponge miR-6837-3p to upregulate MAVS expression, thereby activating type I IFN signaling and promoting anti-tumor immunity. Delivery of circRERE-AAV elicits significant anti-tumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of CRC.  Conclusions: These results uncover modulatory axis constituting of EP300/circRERE/miR-6837-3p/MAVS and its essential roles in anti-tumor immunity, and demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in clinic. Overall design: RNA-seq performed in this study was designed to understand the molecular mechanisms underlying SiNC/sicircRERE in gene transcriptional activation.