PERK-mediated induction of miR-5p and miR-3p arms of miR-616 regulates cell growth by targeting c-MYC

C/EBP homologous protein (CHOP), also known as DNA damage-inducible transcript 3 (DDIT3), is a member of CCAAT/enhancer-binding protein (C/EBP) family. The expression of CHOP is upregulated during unfolded protein response (UPR), and sustained CHOP activity plays an important role in UPR-induced apoptosis. MicroRNA-616 is localized in an intron of the CHOP gene. However, regulation of miR-616 expression during UPR and its function in breast cancer is not clearly understood. We show that miR-5p/-3p arms of miR-616 are expressed with levels of 5p arm higher than 3p arm. During conditions of UPR, the expression of miR-5p and miR-3p arms of miR-616 and its host gene (CHOP) was concordantly increased primarily in a PERK-dependent manner. We show that ectopic expression of miR-616 significantly suppressed cell growth and colony formation, whereas knockout of miR-616 increased it. We identified that MYC proto-oncogene (c-MYC) gene is repressed during the UPR and targeted by miR-616. Further, we show that expression of miR-616 and CHOP is downregulated in human breast cancer, where expression of miR-616 was associated with poor overall survival (OS) in luminal A subtype and better OS HER2 subtype of breast cancer. In summary, our results suggest a dual function for the DDIT3 locus, where CHOP protein and miR-616 can co-operate to regulate cancer progression.