Inflammation and DNA methylation-dependent down-regulation of miR-34b-5p mediates c-MYC expression and CRL4 DCAF4 E3 ligase activity in colitis-associated cancer.

microRNAs (miRNAs), a well-known group of noncoding RNAs, contribute to the pathogenesis of multiple diseases, including colitis-associated cancer (CAC). Our recent findings indicate that proinflammatory cytokines up-regulate c-MYC level, which subsequently activates Cullin 4A and 4B (CUL4A/4B) and CRL4 E3 ligases and promotes ubiquitination of suppression of tumorigenicity 7 (STM7) in CAC. Here, we identified and proved that miR-34b-5p can directly target c-MYC. In vitro oncogenic phenotype analyses and in vivo tumor formation assay indicated that miR-34b-5p overexpression could markedly decrease cell proliferation, colony formation, cell invasion, and tumor volumes. Overexpression of c-MYC in vitro could reverse the oncogenic phenotypes caused by miR-34b-5p up-regulation. Additionally, the down-regulation of miR-34b-5p in CAC was dependent on the coregulation of the inflammatory microenvironment and DNA methylation. Collectively, our findings demonstrate that intracellular inflammation and DNA hypermethylation suppress miR-34b-5p expression, which limits its inhibitory effect on c-MYC and initiates the downstream events, including the induction of CRL4 E3 ligase activity. The activated CRL4 E3 ligase ubiquitinates ST7 and results in its degradation, eventually leading to the CAC tumorigenesis.