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A Notch1–neuregulin1 autocrine signaling loop contributes to melanoma growth

Oncogene volume 31, pages 4609–4618 (2012)Cite this article

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Abstract

The Notch pathway is an evolutionary conserved signaling cascade that has an essential role in melanoblast and melanocyte stem cell homeostasis. Notch signaling is emerging as a key player in melanoma, the most deadly form of skin cancer. In melanoma, Notch1 is inappropriately reactivated and contributes to melanoma tumorigenicity. Here, we propose a novel mechanism by which Notch1 promotes the disease. We found that Notch1 directly regulates the transcription of neuregulin1 (NRG1) by binding to its promoter region. NRG1 is the ligand for ERBB3 and 4, members of the epidermal growth factor family of receptors that are involved in the genesis and progression of a number of cancers. Notch1 and NRG1 expression are associated in melanoma and inhibition of NRG1 signaling leads to melanoma cell growth inhibition and tumor growth delay. Mechanistically, these effects are associated with the inhibition of the PI3Kinase/Akt signaling pathway and with the accumulation of p27Kip1. On the other end, addition of recombinant NRG1 can partially restore melanoma cell growth that is inhibited by Notch1 ablation. Taken together, our findings underline a new, previously undescribed autocrine signaling loop between Notch1 and NRG1 that controls melanoma growth and provide experimental evidence that the targeting of Notch and ERBB signaling may represent a novel potential therapeutic approach in melanoma.

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Acknowledgements

This work was supported in part by Grant # ACS-IRG-91-022 and Grant # ACS-RSG-11-139-01-DDC from the American Cancer Society and by start up funds awarded by the National Institute of Health (award number: P30CA147877: New Faculty Recruitment to Enhance Melanoma Research). We thank Drs Scott Welford and David Samols for critical discussion; Dr Marianne Broome Powell for making available many of the melanoma cell lines used in this work.

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  1. K Zhang and P Wong: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    K Zhang, P Wong, L Zhang & B Bedogni

  2. Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, USA

    B Jacobs & E C Borden

  3. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    J C Aster

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Correspondence to B Bedogni.

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Zhang, K., Wong, P., Zhang, L. et al. A Notch1–neuregulin1 autocrine signaling loop contributes to melanoma growth. Oncogene 31, 4609–4618 (2012). https://doi.org/10.1038/onc.2011.606

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