AGR2 is controlled by DNMT3a-centered signaling module and mediates tumor resistance to 5-Aza in colorectal cancer.

Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is upregulated in various human cancers and reportedly has oncogenic activities. However, the functional roles of AGR2 and its regulation in colorectal cancer (CRC) remain unclear. Here, we showed that AGR2 promoted CRC tumorigenesis and progression in vitro and in vivo and acted as an independent prognostic factor of poor outcome. AGR2 was negatively regulated by DNA methyltransferase 3a (DNMT3a) through directly methylating AGR2 promoter and by a DNMT3a–SPRY2–miR-194 axis. Moreover, AGR2 mediated the resistance to 5-Aza-2′-deoxycytidine (5-Aza) treatment. Knockdown of AGR2 improved the therapeutic effect of 5-Aza in human CRC xenograft tumor model. Thus, our work supports AGR2's oncogenic role in CRC, reveals DNMT3a-mediated epigenetic modulation on AGR2 promoter, and uncovers a new DNMT3a signaling module controlling expression of AGR2. Upregulated AGR2 offset 5-Aza mediated epigenetic therapy. This work might provide potential targets for clinical anti-cancer therapy. • AGR2 acted as an oncogene in CRC. • AGR2 was downregulated by DNMT3a in a dual manner: AGR2 promoter methylation and a DNMT3a–SPRY2–miR-194 signaling axis. • AGR2 mediated the drug resistance of 5-Aza in CRC. AGR2 knockdown could improve the therapeutic effect of 5-Aza in CRC. [ABSTRACT FROM AUTHOR]