MicroRNAs Restrain Proliferation in BRAF V600E Melanocytic Nevi

Benign melanocytic nevi commonly form when melanocytes that acquire a mutation undergo a period of rapid proliferation and subsequent arrest. Constitutive activation of MAPK signaling downstream of BRAF drives the initial proliferative phenotype. However, the factors that establish and maintain growth arrest in nevi remain elusive. The growth-arrested state of melanocytes is not conferred by additional genetic mutations, suggesting a role for regulatory elements. We investigated the role of microRNAs in the initiation and maintenance of nevus arrest. Using primary human melanocytes, melanocytic nevi, and adjacent melanoma, we show that MIR211-5p and MIR328-3p are enriched in nevi compared to normal melanocytes, then subsequently downregulated in adjacent melanoma. Both MIR211-5p and MIR328-3p proved necessary effectors of BRAF-induced growth arrest in human melanocytes. We identified microRNA target networks which, when suppressed, phenocopy BRAF-induced arrest and converge on inhibition of AURKB to block cell cycle progression in primary human melanocytes.