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 language | English (US) |
|---|---|
| Pages (from-to) | 4609-4618 |
| Number of pages | 10 |
| Journal | Oncogene |
| Volume | 31 |
| Issue number | 43 |
| DOIs | |
| State | Published - Oct 25 2012 |
| Externally published | Yes |
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Keywords
- ERBB: erythroblastic leukemia viral oncogene homolog or EGF (epidermal growth factor) family of transmembrane receptor tyrosine kinases
- NIC: Notch1 intracellular domain
- Notch1-TM: transmembrane Notch1
- NRG1: neuregulin1
- p27KIP1: CDKN1B: cyclin-dependent kinase inhibitor 1B
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research
Cite this
A Notch1neuregulin1 autocrine signaling loop contributes to melanoma growth. / Zhang, K.; Wong, P.; Zhang, L.; Jacobs, B.; Borden, E. C.; Aster, J. C.; Bedogni, Barbara.
In: Oncogene, Vol. 31, No. 43, 25.10.2012, p. 4609-4618.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Notch1neuregulin1 autocrine signaling loop contributes to melanoma growth
AU - Zhang, K.
AU - Wong, P.
AU - Zhang, L.
AU - Jacobs, B.
AU - Borden, E. C.
AU - Aster, J. C.
AU - Bedogni, Barbara
PY - 2012/10/25
Y1 - 2012/10/25
N2 - 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.
AB - 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.
KW - ERBB: erythroblastic leukemia viral oncogene homolog or EGF (epidermal growth factor) family of transmembrane receptor tyrosine kinases
KW - NIC: Notch1 intracellular domain
KW - Notch1-TM: transmembrane Notch1
KW - NRG1: neuregulin1
KW - p27KIP1: CDKN1B: cyclin-dependent kinase inhibitor 1B
UR - http://www.scopus.com/inward/record.url?scp=84867897035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867897035&partnerID=8YFLogxK
U2 - 10.1038/onc.2011.606
DO - 10.1038/onc.2011.606
M3 - Article
C2 - 22249266
AN - SCOPUS:84867897035
VL - 31
SP - 4609
EP - 4618
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 43
ER -