Transcription factor/microRNA axis blocks melanoma invasion program by miR-211 targeting NUAK1.
Melanoma is one of the deadliest human cancers, responsible for approximately 80% of skin cancer mortalities. The aggressiveness of melanoma is due to its capacity to proliferate and rapidly invade surrounding tissues, leading to metastases. A recent model suggests melanoma progresses by reversibly switching between proliferation and invasion transcriptional signatures. Recent studies show that cancer cells are more sensitive to microRNA (miRNA) perturbation than are non-cancer cells; however, the roles of miRNAs in melanoma plasticity remain unexplored. Here, we use the gene expression profiles of melanoma and normal melanocytes to characterize the transcription factor-miRNA relationship that modulates the proliferative and invasive programs of melanoma. We identified two sets of miRNAs that likely regulate these programs. Interestingly, one of the miRNAs involved in melanoma invasion is miR-211, a known target of the master regulator microphthalmia-associated transcription factor (MITF). We demonstrate that miR-211 contributes to melanoma adhesion by directly targeting a gene, NUAK1. Inhibition of miR-211 increases NUAK1 expression and decreases melanoma adhesion, whereas upregulation of miR-211 restores adhesion through NUAK1 repression. This study defines the MITF/miR-211 axis that inhibits the invasive program by blocking adhesion. Furthermore, we have identified NUAK1 as a potential target for the treatment of metastatic melanoma.
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Rachel E
RE
Bell
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Mehdi
M
Khaled
Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
Dvir
D
Netanely
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Steffen
S
Schubert
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Tamar
T
Golan
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Amir
A
Buxbaum
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Maja M
MM
Janas
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Benny
B
Postolsky
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Michael S
MS
Goldberg
Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
Ron
R
Shamir
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: carmitlevy@post.tau.ac.il.
Carmit
C
Levy
D001665:Binding Sites / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000556:secondary*; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D014407:Tumor Cells, Cultured
C549405:MIRN211 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D014157:Transcription Factors; D011494:Protein Kinases; C470845:NUAK1 protein, human