miR-210-3p mediates metabolic adaptation and sustains DNA damage repair of resistant colon cancer cells to treatment with 5-fluorouracil

Chemoresistance is the primary cause of chemotherapy failure. Compelling evidenceshows that micro RNAs (miRNAs) contribute to reprogram cancer cells toward aresistant phenotype. We investigate the role of miRNAs in the response to acutetreatment with 5‐FU in colon cancer‐resistant cells. We performed a global geneexpression profile for the entire miRNA genome and found a change in the expressionof four miRNAs following acute treatment with 5‐FU. Among them, we focused onmiR‐210‐3p, previously described as a key regulator of DNA damage repairmechanisms and mitochondrial metabolism. We show that miR‐210‐3p down-regulation enables resistant cells to counteract the toxic effect of the drug increasingthe expression of RAD‐52 protein, responsible for DNA damage repair. Moreover,miR‐210‐3p downregulation enhances oxidative phosphorylation (OXPHOS), increas-ing the expression levels of succinate dehydrogenase subunits D, decreasingintracellular succinate levels and inhibiting HIF ‐1α expression. Altogether, theseadaptations lead to increased cells survival following drug exposure. These evidencesuggest that miR‐210‐3p downregulation following 5‐FU sustains DNA damage repairand metabolic adaptation to counteract drug treatment.