A circular RNA from APC inhibits the proliferation of diffuse large B-cell lymphoma by inactivating Wnt/β-catenin signaling via interacting with TET1 and miR-888

Circular RNA (circRNA), a type of non-coding RNA, can promote or suppress tumorigenesis. To investigate the involvement of circRNA in diffuse large B-cell lymphoma (DLBCL), we performed a circRNA microarray analysis on paired DLBCL and normal tissues. We identified a novel and highly stable circRNA originating from the back-splicing of APC exon 7 to exon 14, circ-APC (hsa_circ_0127621), which was downregulated in DLBCL tissues, cell lines and plasma. In gain-of-function experiments, ectopic expression of circ-APC inhibited DLBCL cell proliferation in vitro and tumor growth in vivo. Cytoplasmic circ-APC functioned as a sponge for miR-888, thus post-transcriptionally upregulating APC by alleviating the repressive effects of miR-888 on this gene. Further, nuclear circ-APC bound to the APC promoter and recruited the DNA demethylase TET1, thereby transcriptionally upregulating APC. Upon its upregulation, APC dampened the canonical Wnt/beta-catenin signaling pathway by reducing the accumulation of beta-catenin in the nucleus, thereby retarding DLBCL growth. Clinically, circ-APC was found to be an effective diagnostic and prognostic biomarker for patients with DLBCL. Our study suggests that circ-APC is a novel proliferation inhibitor, and that restoring circ-APC expression may be a promising therapeutic approach for DLBCL patients.