Abstract
Simple SummaryApproximately 60% of all melanomas are associated with a constitutive activating BRAF mutation. Inhibition of BRAF downstream signaling by targeted therapies significantly improved patient outcomes. However, most patients eventually develop resistance. Here we identified miR-129-5p as a novel tumor suppressor in BRAF mutated melanoma, which expression is increased during response to BRAF inhibition, but repressed in an EZH2 dependent manner during activated BRAF signaling. Overexpression of miR-129-5p decreases melanoma cell proliferation and improves response to BRAF inhibition by targeting SOX4. Taken together our results emphasize SOX4 as a potential therapeutic target in BRAF driven melanoma which could be attacked by pharmaceutically.Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.
Highlights
Melanoma is the most lethal form of skin cancer with an increasing incidence [1]
We compared the miRNA expression of parental A375 cells treated with Vemurafenib to three different conditions: parental A375 cells treated with DMSO, a resistant clone of A375 cells (A375R) treated with Vemurafenib and A375R treated with DMSO
We could confirm our data analysis by virtue of a second published dataset (GSE98314) encompassing 11 BRAF mutated cell lines treated with BRAF inhibitor (BRAFi) (Dabrafenib) or BRAFi/MEK inhibitor (MEKi) (Dabrafenib/Trametinib) and DMSO treated controls: when we performed a comparative analysis, we found that miR-129-5p expression construct (miR-129) expression is induced under BRAFi or BRAFi/MEKi in 10 out of 11 cell lines (Figure 1B)
Summary
Melanoma is the most lethal form of skin cancer with an increasing incidence [1]. IV melanoma has a poor prognosis for patients, with a 5-year survival probability of less than 5–25%, if untreated [2,3]. Progression of a majority of cutaneous melanomas depends on oncogenic, partially mutually exclusive somatic mutations involving BRAF (50–60%), NRAS (20–26%), TP53 (19%), or PTEN (12%) [4,5,6,7,8]. The most common BRAF mutation is the V600E (90%) substitution, which constitutively activates aberrant BRAF signaling [9]. BRAF-mutant melanomas have become amenable to new targeted therapies based on initially BRAF inhibitor (BRAFi) and on its combination with a MEK inhibitor (MEKi).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
