RARβ Acts As Both an Upstream Regulator and Downstream Effector of Mir‐22 , Which Epigenetically Regulates NUR77 to Induce Apoptosis of Colon Cancer Cells

This study investigates the mechanism and consequences of microRNA-22 (miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor (RAR) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RAR and nerve growth factor IB (NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RAR and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RAR and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RAR were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RAR viamiR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RAR acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.