Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma
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 h...
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| Veröffentlicht in: | The Journal of biological chemistry 2009-09, Vol.284 (38), p.26194-26206 |
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| creator | Dobroff, Andrey S. Wang, Hua Melnikova, Vladislava O. Villares, Gabriel J. Zigler, Maya Huang, Li Bar-Eli, Menashe |
| description | 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. |
| doi_str_mv | 10.1074/jbc.M109.019836 |
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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.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M109.019836</identifier><identifier>PMID: 19632997</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Angiogenesis ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell migration ; Chromatin ; Cyclic AMP response element-binding protein ; Cyclic AMP Response Element-Binding Protein - genetics ; Cyclic AMP Response Element-Binding Protein - metabolism ; CYR61 protein ; Cysteine-Rich Protein 61 - genetics ; Cysteine-Rich Protein 61 - metabolism ; DNA microarrays ; Gene Expression Regulation, Enzymologic - genetics ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genes, Tumor Suppressor ; Humans ; Immunoprecipitation ; Matrix Metalloproteinase 2 - biosynthesis ; Matrix Metalloproteinase 2 - genetics ; Melanoma ; Melanoma - genetics ; Melanoma - metabolism ; Melanoma - pathology ; Metastases ; Mice ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Transplantation ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - metabolism ; Promoters ; Transcription ; Transcription, Chromatin, and Epigenetics ; Transplantation, Heterologous ; Tumor suppressor genes ; Tumors</subject><ispartof>The Journal of biological chemistry, 2009-09, Vol.284 (38), p.26194-26206</ispartof><rights>2009 © 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2009 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-ecd52c35172f2083c0375160f27efc7615acf5fb7cd1bdcc9b5c88b4a2f4ac853</citedby><cites>FETCH-LOGICAL-c525t-ecd52c35172f2083c0375160f27efc7615acf5fb7cd1bdcc9b5c88b4a2f4ac853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758018/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758018/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19632997$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dobroff, Andrey S.</creatorcontrib><creatorcontrib>Wang, Hua</creatorcontrib><creatorcontrib>Melnikova, Vladislava O.</creatorcontrib><creatorcontrib>Villares, Gabriel J.</creatorcontrib><creatorcontrib>Zigler, Maya</creatorcontrib><creatorcontrib>Huang, Li</creatorcontrib><creatorcontrib>Bar-Eli, Menashe</creatorcontrib><title>Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>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.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Chromatin</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Cyclic AMP Response Element-Binding Protein - genetics</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>CYR61 protein</subject><subject>Cysteine-Rich Protein 61 - genetics</subject><subject>Cysteine-Rich Protein 61 - metabolism</subject><subject>DNA microarrays</subject><subject>Gene Expression Regulation, Enzymologic - genetics</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Silencing</subject><subject>Genes, Tumor Suppressor</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Matrix Metalloproteinase 2 - biosynthesis</subject><subject>Matrix Metalloproteinase 2 - genetics</subject><subject>Melanoma</subject><subject>Melanoma - genetics</subject><subject>Melanoma - metabolism</subject><subject>Melanoma - pathology</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Transplantation</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neovascularization, Pathologic - metabolism</subject><subject>Promoters</subject><subject>Transcription</subject><subject>Transcription, Chromatin, and Epigenetics</subject><subject>Transplantation, Heterologous</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1vEzEQxVcIRNPCmRvsASE4bOrxrr8ulUoUSqVGVE0rwcnyemcTV7vrYCet-O9xtBEfB4QvtjS_eTNPz1n2CsgUiKhO72s7XQBRUwJKlvxJNgEiy6Jk8PVpNiGEQqEok0fZcYz3JJ1KwfPsCBQvqVJikg1L1-Fg3bDK7fniuggYN36ImM877HHYFrUbmn31OvgtuiF_P7uZf_yQXzap6FqHMZ99u-GQm5ib_HbX-5Avd5tN0onpeYED5qlrgZ0ZfG9eZM9a00V8ebhPsrtP89vZ5-Lqy8Xl7PyqsIyybYG2YdQmF4K2NBmypBQMOGmpwNYKDszYlrW1sA3UjbWqZlbKujK0rYyVrDzJzkbdza7usbFp2WA6vQmuN-GH9sbpvyuDW-uVf9BUMElAJoF3B4Hgv-8wbnXvosUu2UC_i5oLXilG4b8gBeCKcZXA0xG0wccYsP21DRC9D1OnMPU-TD2GmTpe_2niN39ILwFvR2DtVutHF1DXzts19prKSpdSUw6qStibEWuN12YVXNR3S0qgJMCFkGQ_SY0EpkweHAYdrUvfApskare68e6fW_4EFknD9Q</recordid><startdate>20090918</startdate><enddate>20090918</enddate><creator>Dobroff, Andrey S.</creator><creator>Wang, Hua</creator><creator>Melnikova, Vladislava O.</creator><creator>Villares, Gabriel J.</creator><creator>Zigler, Maya</creator><creator>Huang, Li</creator><creator>Bar-Eli, Menashe</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090918</creationdate><title>Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma</title><author>Dobroff, Andrey S. ; Wang, Hua ; Melnikova, Vladislava O. ; Villares, Gabriel J. ; Zigler, Maya ; Huang, Li ; Bar-Eli, Menashe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c525t-ecd52c35172f2083c0375160f27efc7615acf5fb7cd1bdcc9b5c88b4a2f4ac853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Chromatin</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Cyclic AMP Response Element-Binding Protein - genetics</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>CYR61 protein</topic><topic>Cysteine-Rich Protein 61 - genetics</topic><topic>Cysteine-Rich Protein 61 - metabolism</topic><topic>DNA microarrays</topic><topic>Gene Expression Regulation, Enzymologic - genetics</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Silencing</topic><topic>Genes, Tumor Suppressor</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Matrix Metalloproteinase 2 - biosynthesis</topic><topic>Matrix Metalloproteinase 2 - genetics</topic><topic>Melanoma</topic><topic>Melanoma - genetics</topic><topic>Melanoma - metabolism</topic><topic>Melanoma - pathology</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Transplantation</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>Neovascularization, Pathologic - metabolism</topic><topic>Promoters</topic><topic>Transcription</topic><topic>Transcription, Chromatin, and Epigenetics</topic><topic>Transplantation, Heterologous</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dobroff, Andrey S.</creatorcontrib><creatorcontrib>Wang, Hua</creatorcontrib><creatorcontrib>Melnikova, Vladislava O.</creatorcontrib><creatorcontrib>Villares, Gabriel J.</creatorcontrib><creatorcontrib>Zigler, Maya</creatorcontrib><creatorcontrib>Huang, Li</creatorcontrib><creatorcontrib>Bar-Eli, Menashe</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dobroff, Andrey S.</au><au>Wang, Hua</au><au>Melnikova, Vladislava O.</au><au>Villares, Gabriel J.</au><au>Zigler, Maya</au><au>Huang, Li</au><au>Bar-Eli, Menashe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2009-09-18</date><risdate>2009</risdate><volume>284</volume><issue>38</issue><spage>26194</spage><epage>26206</epage><pages>26194-26206</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19632997</pmid><doi>10.1074/jbc.M109.019836</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Angiogenesis Animals Apoptosis Cell Line, Tumor Cell migration Chromatin Cyclic AMP response element-binding protein Cyclic AMP Response Element-Binding Protein - genetics Cyclic AMP Response Element-Binding Protein - metabolism CYR61 protein Cysteine-Rich Protein 61 - genetics Cysteine-Rich Protein 61 - metabolism DNA microarrays Gene Expression Regulation, Enzymologic - genetics Gene Expression Regulation, Neoplastic Gene Silencing Genes, Tumor Suppressor Humans Immunoprecipitation Matrix Metalloproteinase 2 - biosynthesis Matrix Metalloproteinase 2 - genetics Melanoma Melanoma - genetics Melanoma - metabolism Melanoma - pathology Metastases Mice Mice, Nude Neoplasm Metastasis Neoplasm Transplantation Neovascularization, Pathologic - genetics Neovascularization, Pathologic - metabolism Promoters Transcription Transcription, Chromatin, and Epigenetics Transplantation, Heterologous Tumor suppressor genes Tumors |
| title | Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma |
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