Ectopic SOX9 Mediates Extracellular Matrix Deposition Characteristic of Organ Fibrosis

• Published in: The Journal of biological chemistry Vol. 283; no. 20; pp. 14063 - 14071
• Main Authors: Piper Hanley, Karen, Oakley, Fiona, Sugden, Sarah, Wilson, David I., Mann, Derek A., Hanley, Neil A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-05-2008; American Society for Biochemistry and Molecular Biology
• Subjects: Base Sequence; CCAAT-Binding Factor - metabolism; Cell Line, Tumor; Collagen - chemistry; Extracellular Matrix - metabolism; Fibrosis - pathology; Gene Silencing; HeLa Cells; Hepatocytes - cytology; Hepatocytes - metabolism; High Mobility Group Proteins - biosynthesis; High Mobility Group Proteins - metabolism; Histone Deacetylase Inhibitors; Humans; Models, Biological; Molecular Sequence Data; Sequence Homology, Nucleic Acid; SOX9 Transcription Factor; Transcription Factors - biosynthesis; Transcription Factors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M707390200

Appropriate temporospatial expression of the transcription factor SOX9 is important for normal development of a wide range of organs. Here, we show that when SOX9 is expressed ectopically, target genes become expressed that are associated with disease. Histone deacetylase inhibitors in clinical trials for cancer therapy induced SOX9 expression via enhanced recruitment of nuclear factor Y (NF-Y) to CCAAT elements in the SOX9 proximal promoter. The effect of histone deacetylase inhibitors could be elicited in cells that normally lack SOX9, such as hepatocytes. In human fetal hepatocytes, this aberrant induction of SOX9 protein caused ectopic expression of COL2A1 and COMP1 that encode extracellular matrix (ECM) components normally associated with chondrogenesis. Previously, ectopic expression of this “chondrogenic” profile has been implicated in vascular calcification. More broadly, inappropriate ECM deposition is a hallmark of fibrosis. We demonstrated that induction of SOX9 expression also occurred during activation of fibrogenic cells from the adult liver when the transcription factor was responsible for expression of the major component of fibrotic ECM, type 1 collagen. These combined data identify new aspects in the regulation of SOX9 expression. They support a role for SOX9 beyond normal development as a transcriptional regulator in the pathology of fibrosis.