ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways

Laboratory Investigation (2020)Cite this article

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Abstract

Activating transcription factor 3 (ATF-3), a cyclic AMP-dependent transcription factor, has been shown to play a regulatory role in melanoma, although its function during tumor progression remains unclear. Here, we demonstrate that ATF-3 exhibits tumor suppressive function in melanoma. Specifically, ATF-3 nuclear expression was significantly diminished with melanoma progression from nevi to primary to metastatic patient melanomas, correlating low expression with poor prognosis. Significantly low expression of ATF-3 was also found in cultured human metastatic melanoma cell lines. Importantly, overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited cell growth, migration, and invasion in vitro; as well as abrogated tumor growth in a human melanoma xenograft mouse model in vivo. RNA sequencing analysis revealed downregulation of ERK and AKT pathways and upregulation in apoptotic-related genes in ATF-3 overexpressed melanoma cell lines, which was further validated by Western-blot analysis. In summary, this study demonstrated that diminished ATF-3 expression is associated with melanoma virulence and thus provides a potential target for novel therapies and prognostic biomarker applications.

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Fig. 1: ATF3 expression decreased in melanoma.
Fig. 2: ATF3 over-expression inhibited melanoma cell growth, migration and invasion.
Fig. 3: ATF3 over-expression inhibits melanoma tumor formation and growth in vivo.
Fig. 4: ATF3 over-expression inhibits melanoma cell growth, migration and invasion by down regulating ERK and AKT phosphorylation.

Data availability

The RNA-sequencing data have been deposited to the NCBI Gene Expression Omnibus under accession number GSE152460.

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Acknowledgements

This work was supported to XW by the National Key Research and Development Program of China (2017YFA0104604), the General Program of National Natural Science Foundation of China (81772093), the Key Program of Shandong Province Natural Science Foundation (ZR2019ZD36) and the Key Research and Development Program of Shandong Province (2019GSF108107). CAAL is currently funded by T32 EB016652-06.

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Author notes

  1. These authors contributed equally: Tingjian Zu, Diana Wang

  2. These authors contributed equally as corresponding authors: Xunwei Wu, Christine G. Lian, George F. Murphy

Affiliations

  1. Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shangdong, China

    Tingjian Zu, Shuangshuang Wang & Xunwei Wu

  2. School of Stomatology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an, Shangdong, China

    Tingjian Zu

  3. Department of Pathology, Program in Dermatopathology, Brigham and Women’s Hospital, Boston, MA, USA

    Tingjian Zu, Diana Wang, Shuyun Xu, Ellen Zhen, Phammela Abarzua, Christine G. Lian & George F. Murphy

  4. Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA, USA

    Diana Wang

  5. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Catherine A. A. Lee & Natasha Y. Frank

  6. Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA

    Charles H. Yoon

  7. Department of Medicine, VA Boston Healthcare System, Boston, MA, USA

    Natasha Y. Frank

  8. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

    Natasha Y. Frank & George F. Murphy

  9. Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA, USA

    Xunwei Wu

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  1. Tingjian Zu
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Zu, T., Wang, D., Xu, S. et al. ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways. Lab Invest (2020). https://doi.org/10.1038/s41374-020-00516-y

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