Abstract
Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway.By performing small RNA sequencing on A375 melanoma cells and a vemurafenib-resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib's anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib's pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the efficacy of vemurafenib.In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.
Highlights
BRAF is a Ser/Thr protein kinase belonging to the highly oncogenic RAS/RAF/MEK/ERK signaling pathway
Clustering analysis indicated that the only condition that is different from the others is the one in which vemurafenib is able to inhibit BRAFV600E and block the ERK pathway in A375 parental cells (Figure 2b)
We selected as BRAFV600Eregulated miRNAs those that showed increased or www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget decreased expression levels in A375 cells treated with vemurafenib and comparable levels in the other three conditions
Summary
BRAF is a Ser/Thr protein kinase belonging to the highly oncogenic RAS/RAF/MEK/ERK signaling pathway. BRAFi such as vemurafenib have been shown to increase overall and progression-free survival in metastatic melanoma patients who carry the V600E mutation. These inhibitors have significant limitations, including: suboptimal response rates, which occur in setting of adaptive cellular responses [2,3,4,5,6]; a heterogeneous response rate among patient populations; severe side effects that often require treatment termination; invariable development of acquired resistance within 6 months of treatment initiation [7, 8]. Novel approaches to enhance BRAFi efficacy are still needed [9, 10]
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