Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma
Open accessAbstract
Metastatic progression of melanoma is associated with overexpression and activity of cAMP-response element-binding protein (CREB). However, the mechanism by which CREB contributes to tumor progression and metastasis remains unclear. Here, we demonstrate that stably silencing CREB expression in two human metastatic melanoma cell lines, A375SM and C8161-c9, suppresses tumor growth and experimental metastasis. Analysis of cDNA microarrays revealed that CREB silencing leads to increased expression of cysteine-rich protein 61 (CCN1/CYR61) known to mediate adhesion, chemostasis, survival, and angiogenesis. Promoter analysis and chromatin immunoprecipitation assays demonstrated that CREB acts as a negative regulator of CCN1/CYR61 transcription by directly binding to its promoter. Re-expression of CREB in CREB-silenced cells rescued the low CCN1/CYR61 expression phenotype. CCN1/CYR61 overexpression resulted in reduced tumor growth and metastasis and inhibited the activity of matrix metalloproteinase-2. Furthermore, its overexpression decreased melanoma cell motility and invasion through Matrigel, which was abrogated by silencing CCN1/CYR61 in low metastatic melanoma cells. Moreover, a significant decrease in angiogenesis as well as an increase in apoptosis was seen in tumors overexpressing CCN1/CYR61. Our results demonstrate that CREB promotes melanoma growth and metastasis by down-regulating CCN1/CYR61 expression, which acts as a suppressor of melanoma cell motility, invasion and angiogenesis.
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CCN1 expression in melanoma cells reduced tumor growth and metastasis and increased apoptosis in tumors.
“and CCN1 expression in melanoma cells reduced tumor growth and metastasis and concomitantly increased apoptosis in tumors [161].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [161]
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- Authors
- Dobroff, A. S., Wang, H., Melnikova, V. O., Villares, G. J., Zigler, M., Huang, L., & Bar-Eli, M.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 284
- Issue
- 38
- Pages
- 26194-26206
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2758018
- OpenAlex
- W1985126333
- Cited by
- 89
- References
- 61
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 5 · 2015: 8 · 2014: 6 · 2013: 6 · 2012: 8
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Feinberg School of Medicine
- National Cancer Institute (R01CA076098, CA-76098)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- CREB, CYR61, melanoma, tumor suppressor, metastasis, tumor growth, MMP-2, cell motility, cell invasion, angiogenesis, apoptosis, transcriptional regulation
- MeSH terms
- Animals, Humans, Melanoma, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, Transplantation, Heterologous, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Cyclic AMP Response Element-Binding Protein, Matrix Metalloproteinase 2, Gene Silencing, Cell Line, Tumor, Mice, Cysteine-Rich Protein 61
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