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

Lee, Bongyong and Sahoo, Anupama and Sawada, Junko and Marchica, John and Sahoo, Sanjay and Layng, Fabiana I. A. L. and Finlay, Darren and Mazar, Joseph and Joshi, Piyush and Komatsu, Masanobu and Vuori, Kristiina and de Jong, Petrus R. and Ray, Animesh and Perera, Ranjan J. (2020) MicroRNA-211 modulates the DUSP6-ERK5 signaling axis to promote BRAF^(V600E)-driven melanoma growth in vivo and BRAF/MEK inhibitor resistance. Journal of Investigative Dermatology . ISSN 0022-202X. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20200909-065845083

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.jid.2020.06.038DOIArticle
Additional Information:© 2020 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. Received 27 September 2019, Revised 17 June 2020, Accepted 22 June 2020, Available online 2 September 2020.
Record Number:CaltechAUTHORS:20200909-065845083
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200909-065845083
Official Citation: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, MicroRNA-211 modulates the DUSP6-ERK5 signaling axis to promote BRAFV600E-driven melanoma growth in vivo and BRAF/MEK inhibitor resistance, Journal of Investigative Dermatology, 2020, ISSN 0022-202X, https://doi.org/10.1016/j.jid.2020.06.038. (http://www.sciencedirect.com/science/article/pii/S0022202X20320431)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105282
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Sep 2020 17:52
Last Modified:09 Sep 2020 17:52

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