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Ectopic SOX9 Mediates Extracellular Matrix Deposition Characteristic of Organ Fibrosis

Lookup NU author(s): Professor Fiona Oakley, Dr David Wilson, Professor Derek Mann, Dr Neil Hanley

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Abstract

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.


Publication metadata

Author(s): Hanley KP, Oakley F, Sugden S, Wilson DI, Mann DA, Hanley NA

Publication type: Article

Journal: Journal of Biological Chemistry

Year: 2008

Volume: 283

Issue: 20

Pages: 14063-14071

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M707390200

DOI: 10.1074/jbc.M707390200

PubMed id: 18296708


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