MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAFV600E-Driven Melanoma Growth In Vivo and BRAF/MEK Inhibitor Resistance

Bongyong Lee, Anupama Sahoo, Junko Sawada, John Marchica, Sanjay Sahoo, Fabiana I.A.L. Layng, Darren Finlay, Joseph Mazar, Piyush Joshi, Masanobu Komatsu, Kristiina Vuori, Petrus R. de Jong, Animesh Ray, Ranjan J. Perera

Research output: Contribution to journalArticlepeer-review

Abstract

MicroRNAs (miRs) are important posttranscriptional regulators of cell fate in both normal and disease states. miR-211 has previously been shown to be a direct regulator of metabolism in BRAFV600E-mutant melanoma cells in vitro. Here, we report that miR-211 expression promotes the aggressive growth of BRAFV600E-mutant melanoma xenografts in vivo. miR-211 promoted proliferation through the posttranscriptional activation of extracellular signal–regulated kinase (ERK) 5 signaling, which has recently been implicated in the resistance to BRAF and MAPK/ERK kinase inhibitors. We therefore examined whether miR-211 similarly modulated melanoma resistance to the BRAF inhibitor vemurafenib and the MAPK/ERK kinase inhibitor cobimetinib. Consistent with this model, miR-211 expression increased melanoma cell resistance to both the inhibitors, and this resistance was associated with an 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.

Original languageEnglish (US)
Pages (from-to)385-394
Number of pages10
JournalJournal of Investigative Dermatology
Volume141
Issue number2
DOIs
StatePublished - Feb 2021
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Fingerprint Dive into the research topics of 'MicroRNA-211 Modulates the DUSP6-ERK5 Signaling Axis to Promote BRAF<sup>V600E</sup>-Driven Melanoma Growth In Vivo and BRAF/MEK Inhibitor Resistance'. Together they form a unique fingerprint.

Cite this