A Notch1neuregulin1 autocrine signaling loop contributes to melanoma growth

K. Zhang, P. Wong, L. Zhang, B. Jacobs, E. C. Borden, J. C. Aster, B. Bedogni

Research output: Contribution to journalArticle

35 Scopus citations

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 p27 Kip1. 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.

Original languageEnglish (US)
Pages (from-to)4609-4618
Number of pages10
JournalOncogene
Volume31
Issue number43
DOIs
StatePublished - Oct 25 2012
Externally publishedYes

Keywords

  • ERBB: erythroblastic leukemia viral oncogene homolog or EGF (epidermal growth factor) family of transmembrane receptor tyrosine kinases
  • NIC: Notch1 intracellular domain
  • NRG1: neuregulin1
  • Notch1-TM: transmembrane Notch1
  • p27KIP1: CDKN1B: cyclin-dependent kinase inhibitor 1B

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Zhang, K., Wong, P., Zhang, L., Jacobs, B., Borden, E. C., Aster, J. C., & Bedogni, B. (2012). A Notch1neuregulin1 autocrine signaling loop contributes to melanoma growth. Oncogene, 31(43), 4609-4618. https://doi.org/10.1038/onc.2011.606