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Research Article

A genomic screen identifies TYRO3 as a MITF regulator in melanoma

Shoutian Zhu, Heiko Wurdak, Yan Wang, Anna Galkin, Haiyan Tao, Jie Li, Costas A. Lyssiotis, Feng Yan, Buu P. Tu, Loren Miraglia, John Walker, Fanxiang Sun, Anthony Orth, Peter G. Schultz, and Xu Wu
PNAS first published September 23, 2009; https://doi.org/10.1073/pnas.0909292106
Shoutian Zhu
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Heiko Wurdak
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Yan Wang
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Anna Galkin
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Haiyan Tao
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Jie Li
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Costas A. Lyssiotis
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Feng Yan
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Buu P. Tu
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Loren Miraglia
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John Walker
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Fanxiang Sun
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Anthony Orth
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Peter G. Schultz
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  • For correspondence: schultz@scripps.edu xwu@gnf.org
Xu Wu
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  • For correspondence: schultz@scripps.edu xwu@gnf.org
  1. ↵1H.W. and Y.W. contributed equally to this work.

  2. Contributed by Peter G. Schultz, August 19, 2009 (sent for review July 1, 2009)

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Abstract

Malignant melanoma is the most aggressive form of cutaneous carcinoma, accounting for 75% of all deaths caused by skin cancers. Microphthalmia-associated transcription factor (MITF) is a master gene regulating melanocyte development and functions as a “lineage addiction” oncogene in malignant melanoma. We have identified the receptor protein tyrosine kinase TYRO3 as an upstream regulator of MITF expression by a genome-wide gain-of-function cDNA screen and show that TYRO3 induces MITF-M expression in a SOX10-dependent manner in melanoma cells. Expression of TYRO3 is significantly elevated in human primary melanoma tissue samples and melanoma cell lines and correlates with MITF-M mRNA levels. TYRO3 overexpression bypasses BRAF(V600E)-induced senescence in primary melanocytes, inducing transformation of non-tumorigenic cell lines. Furthermore, TYRO3 knockdown represses cellular proliferation and colony formation in melanoma cells, and sensitizes them to chemotherapeutic agent-induced apoptosis; TYRO3 knockdown in melanoma cells also inhibits tumorigenesis in vivo. Taken together, these data indicate that TYRO3 may serve as a target for the development of therapeutic agents for melanoma.

Footnotes

  • 2To whom correspondence may be addressed. E-mail: schultz{at}scripps.edu or xwu{at}gnf.org
  • Author contributions: S.Z., H.W., P.G.S., and X.W. designed research; S.Z., H.W., Y.W., A.G., H.T., J.L., F.Y., and B.P.T. performed research; S.Z., H.W., Y.W., A.G., H.T., C.A.L., L.M., J.W., F.S., A.O., P.G.S., and X.W. analyzed data; and S.Z., H.W., C.A.L., P.G.S., and X.W. wrote the paper.

  • The authors declare no conflict of interest.

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A genomic screen identifies TYRO3 as a MITF regulator in melanoma
Shoutian Zhu, Heiko Wurdak, Yan Wang, Anna Galkin, Haiyan Tao, Jie Li, Costas A. Lyssiotis, Feng Yan, Buu P. Tu, Loren Miraglia, John Walker, Fanxiang Sun, Anthony Orth, Peter G. Schultz, Xu Wu
Proceedings of the National Academy of Sciences Sep 2009, pnas.0909292106; DOI: 10.1073/pnas.0909292106

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A genomic screen identifies TYRO3 as a MITF regulator in melanoma
Shoutian Zhu, Heiko Wurdak, Yan Wang, Anna Galkin, Haiyan Tao, Jie Li, Costas A. Lyssiotis, Feng Yan, Buu P. Tu, Loren Miraglia, John Walker, Fanxiang Sun, Anthony Orth, Peter G. Schultz, Xu Wu
Proceedings of the National Academy of Sciences Sep 2009, pnas.0909292106; DOI: 10.1073/pnas.0909292106
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