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The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells
- Source :
- International Journal of Molecular Sciences, Vol 22, Iss 11259, p 11259 (2021), International Journal of Molecular Sciences, Volume 22, Issue 20
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the MAPK7 gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, such as proliferation. Hedgehog-GLI signalling is constitutively active in melanoma and is required for proliferation. However, no data are available in literature about a possible interplay between Hedgehog-GLI and ERK5 pathways. Here, we show that hyperactivation of the Hedgehog-GLI pathway by genetic inhibition of the negative regulator Patched 1 increases the amount of ERK5 mRNA and protein. Chromatin immunoprecipitation showed that GLI1, the major downstream effector of Hedgehog-GLI signalling, binds to a functional non-canonical GLI consensus sequence at the MAPK7 promoter. Furthermore, we found that ERK5 is required for Hedgehog-GLI-dependent melanoma cell proliferation, and that the combination of GLI and ERK5 inhibitors is more effective than single treatments in reducing cell viability and colony formation ability in melanoma cells. Together, these findings led to the identification of a novel Hedgehog-GLI-ERK5 axis that regulates melanoma cell growth, and shed light on new functions of ERK5, paving the way for new therapeutic options in melanoma and other neoplasms with active Hedgehog-GLI and ERK5 pathways.
- Subjects :
- Skin Neoplasms
MAPK7
MAP Kinase Kinase 5
Mice
Biology (General)
Spectroscopy
integumentary system
Effector
Melanoma
General Medicine
targeted therapy
Computer Science Applications
Gene Expression Regulation, Neoplastic
Patched-1 Receptor
Chemistry
embryonic structures
Signal Transduction
Patched
Chromatin Immunoprecipitation
animal structures
Cell Survival
QH301-705.5
Biology
Zinc Finger Protein GLI1
Catalysis
Article
Cell Line
Inorganic Chemistry
GLI1
medicine
melanoma
Animals
Humans
Hedgehog Proteins
Physical and Theoretical Chemistry
Molecular Biology
Hedgehog
ERK5/MAPK7
QD1-999
Mitogen-Activated Protein Kinase 7
Cell Proliferation
Cell growth
Organic Chemistry
GLI
medicine.disease
HEK293 Cells
Cancer research
biology.protein
NIH 3T3 Cells
Chromatin immunoprecipitation
Subjects
Details
- Language :
- English
- ISSN :
- 16616596 and 14220067
- Volume :
- 22
- Issue :
- 11259
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....72daed596238e1b2a1520ac0144862f9