BRAF^V600E induces reversible mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB

Abstract

Benign melanocytic nevi commonly form when melanocytes that acquire a BRAFV600E 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 BRAFV600E 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 BRAFV600E-induced growth arrest in human melanocytes. We identified microRNA target networks which, when suppressed, phenocopy BRAFV600E-induced arrest and converge on inhibition of AURKB to block cell cycle progression in primary human melanocytes.Statement of SignificanceWe describe a microRNA regulatory network that enforces BRAFV600E-induced growth arrest in human melanocytes during melanocytic nevus formation. De-regulation of MIR211-5p and MIR328-3p targets – which converge on AURKB – leads to cell cycle re-entry and melanoma progression. AURKB inhibition therefore provides a potential therapeutic intervention for melanoma prevention or treatment.

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

“…[41][42][43] In addition, BRAF V600E was reported to induce a similar proliferation arrest and senescence in primary human melanocytes via micRNA-mediated suppression of AURKB. 44 While overall these results indicated that OIS acts as a vital brake to slow carcinogenesis, 45 the inflammation induced by OIS can sometimes promote tumor progression.…”