Mutated MITF-E87R in Melanoma Enhances Tumor Progression via S100A4

Alice Nordlinger, Shani Dror, Abdel Elkahloun, Justine Del Rio, Elisa Stubbs, Tami Golan, Hagar Malcov, Todd D. Pricket, Julia C. Cronin, Shivang Parikh, Sapir Labes, Laetitia Thomas, Gal Yankovitz, Yuval Tabach, Carmit Levy, Yardena Samuels, Mehdi Khaled*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Melanoma, a melanocyte origin neoplasm, is the most lethal type of skin cancer, and incidence is increasing. Several familial and somatic mutations have been identified in the gene encoding the melanocyte lineage master regulator, MITF; however, the neoplastic mechanisms of these mutant MITF variants are mostly unknown. Here, by performing unbiased analysis of the transcriptomes in cells expressing mutant MITF, we identified calcium-binding protein S100A4 as a downstream target of MITF-E87R. By using wild-type and mutant MITF melanoma lines, we found that both endogenous wild-type and MITF-E87R variants occupy the S100A4 promoter. Remarkably, whereas wild-type MITF represses S100A4 expression, MITF-E87R activates its transcription. The opposite effects of wild-type and mutant MITF result in opposing cellular phenotypes, because MITF-E87R via S100A4 enhanced invasion and reduced adhesion in contrast to wild-type MITF activity. Finally, we found that melanoma patients with altered S100A4 expression have poor prognosis. These data show that a change in MITF transcriptional activity from repression to activation of S100A4 that results from a point mutation in MITF alters melanoma invasive ability. These data suggest new opportunities for diagnosis and treatment of metastatic melanoma.

Original languageEnglish
Pages (from-to)2216-2223
Number of pages8
JournalJournal of Investigative Dermatology
Volume138
Issue number10
DOIs
StatePublished - Oct 2018

Funding

FundersFunder number
ANR-MMO
ATIP-AVENIR
European Union's Horizon 2020 research and innovation program
Fritz Thyssen Stiftung foundation
US-Israel Binational Science Fund
National Human Genome Research InstituteZICHG200365
Israel Cancer Research Fund
Horizon 2020 Framework Programme677645
European Research CouncilStG-335377
Fritz Thyssen Stiftung
Israel Science Foundation
Israeli Centers for Research Excellence41/11

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