title: Oncogenicity of the developmental transcription factor Sox9.
abstract: SOX9 [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.
authors.affiliation: Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom. ander.matheu@biodonostia.org
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.forename: Manuel
authors.initials: M
authors.lastname: Collado
authors.forename: Clare
authors.initials: C
authors.lastname: Wise
authors.forename: Lorea
authors.initials: L
authors.lastname: Manterola
authors.forename: Lina
authors.initials: L
authors.lastname: Cekaite
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Tye
authors.forename: Marta
authors.initials: M
authors.lastname: Canamero
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.forename: Kathryn S E
authors.initials: KS
authors.lastname: Cheah
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.forename: James
authors.initials: J
authors.lastname: Briscoe
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055758:SOX9 Transcription Factor / Q000502:physiology*
chemical_list: D055758:SOX9 Transcription Factor