MicroRNA-211 modulates the DUSP6-ERK5 signaling axis to promote BRAF^(V600E)-driven melanoma growth in vivo and BRAF/MEK inhibitor resistance

Abstract

Micro-RNAs are important post-transcriptional regulators of cell fate both in normal and disease states. miR-211 has previously been shown to be a direct regulator of metabolism in BRAF^(V600E)-mutant melanoma cells in vitro. Here we report that miR-211 expression promotes aggressive growth of BRAF^(V600E)-mutant melanoma xenografts in vivo. miR-211 promoted proliferation through post-transcriptional activation of ERK5 signaling, which has recently been implicated in BRAF and MEK inhibitor resistance. We therefore examined whether miR-211 similarly modulated melanoma resistance to the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. Consistent with this model, miR-211 expression increased melanoma cell resistance to both inhibitors and this resistance was associated with increased ERK5 phosphorylation. miR-211 mediates these effects by directly inhibiting the expression of DUSP6, an ERK5 pathway-specific phosphatase and now shown to be an miR-211 target gene. These results dissect the role of the miR-211-DUSP6-ERK5 axis in melanoma tumor growth and suggest a mechanism for the development of drug-resistant tumors and a target for overcoming resistance