TY - JOUR
T1 - Transcription factor/microRNA axis blocks melanoma invasion program by miR-211 targeting NUAK1
AU - Bell, Rachel E.
AU - Khaled, Mehdi
AU - Netanely, Dvir
AU - Schubert, Steffen
AU - Golan, Tamar
AU - Buxbaum, Amir
AU - Janas, Maja M.
AU - Postolsky, Benny
AU - Goldberg, Michael S.
AU - Shamir, Ron
AU - Levy, Carmit
N1 - Funding Information:
We gratefully acknowledge the help received from Dr David Fisher in numerous aspects of this work; Dr Carl Novina and Dr Hanah Margalit are thanked for useful discussions. We would like to extend our gratitude to Dr Meenhard Herlyn and Dr Levi Garraway for supplying melanoma short-term cultures for these studies. CL gratefully acknowledges grants from The Israeli Centers for Research Excellence (I-CORE), Israel Cancer Association (ICA), Israel Cancer Research Fund (ICRF), US-Israel Binational Science Fund (BSF), Fritz Thyssen Stiftung, Marie Curie Career Integration Grants (CIG), Dalya Gridinger Fund, Fingerhot Carol, and Lionara Fund, and the Shtacher Family Award. RS was supported in part by a grant from the Israel Cancer Research Fund and by the Raymond and Beverly Sackler Chair in Bioinformatics. DN was supported in part by a fellowship from the Edmond J. Safra Center for Bioinformatics at Tel Aviv University.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892780770&partnerID=8YFLogxK
U2 - 10.1038/jid.2013.340
DO - 10.1038/jid.2013.340
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AN - SCOPUS:84892780770
VL - 134
SP - 441
EP - 451
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 2
ER -