AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma

Takeshi Namiki, Atsushi Tanemura, Julio C. Valencia, Sergio G. Coelho, Thierry Passeron, Masakazu Kawaguchi, Wilfred D. Vieira, Masashi Ishikawa, Wataru Nishijima, Toshiyuki Izumo, Yasuhiko Kaneko, Ichiro Katayama, Yuji Yamaguchi, Lanlan Yin, Eric C. Polley, Hongfang Liu, Yutaka Kawakami, Yoshinobu Eishi, Eishi Takahashi, Hiroo YokozekiVincent J. Hearing

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Abstract

The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase NUAK2 as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify NUAK2 as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan-Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44-10.50; P = 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties.

Original languageEnglish
Pages (from-to)6597-6602
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number16
DOIs
Publication statusPublished - 2011 Apr 19

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Keywords

  • Chromosome 1q
  • Sucrose nonfermenting-like kinase

ASJC Scopus subject areas

  • General

Cite this

Namiki, T., Tanemura, A., Valencia, J. C., Coelho, S. G., Passeron, T., Kawaguchi, M., Vieira, W. D., Ishikawa, M., Nishijima, W., Izumo, T., Kaneko, Y., Katayama, I., Yamaguchi, Y., Yin, L., Polley, E. C., Liu, H., Kawakami, Y., Eishi, Y., Takahashi, E., ... Hearing, V. J. (2011). AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma. Proceedings of the National Academy of Sciences of the United States of America, 108(16), 6597-6602. https://doi.org/10.1073/pnas.1007694108