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Article: Oncogenicity of the developmental transcription factor Sox9

TitleOncogenicity of the developmental transcription factor Sox9
Authors
Issue Date2012
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2012, v. 72 n. 5, p. 1301-1315 How to Cite?
AbstractSOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence, and collaborate with other oncogenes in neoplastic transformation. In primary mouse embryo fibroblasts and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whereas its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly, in colorectal cancer. ©2012 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/152631
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Human Frontier Science Program
Spanish Ministry of Science (MICINN)
UK Medical Research CouncilU117512772
NIH
CNIO
MICINNSAF2005-03018
European Research Council
"Marcelino Botin" Foundation
Research Grants Council
University Grants Council of Hong KongHKU 4/05C
AoE/M-04/04
Funding Information:

A. Matheu was supported by a postdoctoral fellowship from the Human Frontier Science Program. M. Collado is funded by the "Ramon y Cajal" Program from the Spanish Ministry of Science (MICINN). L. Manterola is a Sara Borrell fellow from Carlos III Health Institute. Work in the laboratory of R. Lovell-Badge is funded by the UK Medical Research Council (U117512772) and an NIH Quantum Grant. Work in the laboratory of M. Serrano is funded by the CNIO and by grants from the MICINN (SAF2005-03018 and OncoBIO-CONSOLIDER), from the European Research Council, and from the "Marcelino Botin" Foundation. K. S. E. Cheah is supported by the Research Grants Council and University Grants Council of Hong Kong (HKU 4/05C and AoE/M-04/04).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorMatheu, Aen_US
dc.contributor.authorCollado, Men_US
dc.contributor.authorWise, Cen_US
dc.contributor.authorManterola, Len_US
dc.contributor.authorCekaite, Len_US
dc.contributor.authorTye, AJen_US
dc.contributor.authorCanamero, Men_US
dc.contributor.authorBujanda, Len_US
dc.contributor.authorSchedl, Aen_US
dc.contributor.authorCheah, KSEen_US
dc.contributor.authorSkotheim, RIen_US
dc.contributor.authorLothe, RAen_US
dc.contributor.authorLopez de Munain, Aen_US
dc.contributor.authorBriscoe, Jen_US
dc.contributor.authorSerrano, Men_US
dc.contributor.authorLovell-Badge, Ren_US
dc.date.accessioned2012-07-16T09:44:32Z-
dc.date.available2012-07-16T09:44:32Z-
dc.date.issued2012en_US
dc.identifier.citationCancer Research, 2012, v. 72 n. 5, p. 1301-1315en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/152631-
dc.description.abstractSOX9 [sex-determining region Y (SRY)-box 9 protein], a high mobility group box transcription factor, plays critical roles during embryogenesis and its activity is required for development, differentiation, and lineage commitment in various tissues including the intestinal epithelium. Here, we present functional and clinical data of a broadly important role for SOX9 in tumorigenesis. SOX9 was overexpressed in a wide range of human cancers, where its expression correlated with malignant character and progression. Gain of SOX9 copy number is detected in some primary colorectal cancers. SOX9 exhibited several pro-oncogenic properties, including the ability to promote proliferation, inhibit senescence, and collaborate with other oncogenes in neoplastic transformation. In primary mouse embryo fibroblasts and colorectal cancer cells, SOX9 expression facilitated tumor growth and progression whereas its inactivation reduced tumorigenicity. Mechanistically, we have found that Sox9 directly binds and activates the promoter of the polycomb Bmi1, whose upregulation represses the tumor suppressor Ink4a/Arf locus. In agreement with this, human colorectal cancers showed a positive correlation between expression levels of SOX9 and BMI1 and a negative correlation between SOX9 and ARF in clinical samples. Taken together, our findings provide direct mechanistic evidence of the involvement of SOX9 in neoplastic pathobiology, particularly, in colorectal cancer. ©2012 AACR.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Proliferation-
dc.subject.meshCell Transformation, Neoplastic - genetics-
dc.subject.meshColorectal Neoplasms - genetics-
dc.subject.meshSOX9 Transcription Factor - physiology-
dc.titleOncogenicity of the developmental transcription factor Sox9en_US
dc.typeArticleen_US
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0008-5472&volume=72&spage=1301&epage=1315&date=2012&atitle=Oncogenicity+of+the+Developmental+Transcription+Factor+Sox9en_US
dc.identifier.emailCheah, KSE: hrmbdkc@hku.hken_US
dc.identifier.emailLovell-Badge, R: rlovell@hku.hken_US
dc.identifier.authorityCheah, KSE=rp00342en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-11-3660-
dc.identifier.pmid22246670-
dc.identifier.pmcidPMC3378515-
dc.identifier.scopuseid_2-s2.0-84857700780-
dc.identifier.hkuros200629en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84857700780&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume72en_US
dc.identifier.issue5-
dc.identifier.spage1301en_US
dc.identifier.epage1315en_US
dc.identifier.isiWOS:000300989100029-
dc.publisher.placeUnited States-
dc.relation.projectGenomic approaches to uncover functionally relevant signalling pathways in craniofacial development-
dc.relation.projectDevelopmental genomics and skeletal research-
dc.identifier.scopusauthoridMatheu, A=55050516400en_US
dc.identifier.scopusauthoridCollado, M=55049554100en_US
dc.identifier.scopusauthoridWise, C=55053618000en_US
dc.identifier.scopusauthoridManterola, L=55050246800en_US
dc.identifier.scopusauthoridCekaite, L=55055631900en_US
dc.identifier.scopusauthoridTye, AJ=55056277000en_US
dc.identifier.scopusauthoridCanamero, M=16024123000en_US
dc.identifier.scopusauthoridBujanda, L=7006342405en_US
dc.identifier.scopusauthoridSchedl, A=55049887400en_US
dc.identifier.scopusauthoridCheah, KSE=35387746200en_US
dc.identifier.scopusauthoridSkotheim, RI=55056207400en_US
dc.identifier.scopusauthoridLothe, RA=16171650300en_US
dc.identifier.scopusauthoridDe Munain, AL=55055486400en_US
dc.identifier.scopusauthoridBriscoe, J=55052015400en_US
dc.identifier.scopusauthoridSerrano, M=7201394101en_US
dc.identifier.scopusauthoridLovellBadge, R=55056211900en_US

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