miR-6883 family miRNAs target CDK4/6 to induce G₁ phase cell-cycle arrest in colon cancer cells

CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and The Cancer Genome Atlas dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer. The 3⁰UTR of CDK4/6 mRNAs are targeted by a family of miRNAs, which includes miR-6883-5p, miR-149, miR-6785-5p, and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149 downregulated CDK4 and CDK6 levels in human colorectal cancer cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149 and intronic miRNA-6883-5p encoding the clock gene PER1 in colorectal cancer patient samples. Restoring expression of miR-6883-5p and miR-149 blocked cell growth leading to G₀–G₁ phase cell-cycle arrest and apoptosis in colorectal cancer cells. CDK4/6 targeting by miR-6883-5p and miR-149 could only partially explain the observed antiproliferative effects. Notably, both miRNAs synergized with the frontline colorectal cancer chemotherapy drug irinotecan. Further, they resensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve colorectal cancer management.