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J. Biol. Chem., Vol. 283, Issue 20, 14063-14071, May 16, 2008

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Ectopic SOX9 Mediates Extracellular Matrix Deposition Characteristic of Organ Fibrosis^*

Karen Piper Hanley¹, Fiona Oakley^¶, Sarah Sugden, David I. Wilson, Derek A. Mann^¶, and Neil A. Hanley²

From the Centre for Human Development, Stem Cells & Regeneration, and the Human Genetics Division, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, United Kingdom and the ^¶Liver Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle-upon-Tyne NE2 4HH, United Kingdom

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.

Received for publication, September 4, 2007 , and in revised form, February 22, 2008.

^* The work described in this manuscript has been filed as patent application 0709506.0. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Tables 1-4.

¹ To whom correspondence may be addressed: Human Genetics Division, Duthie Bldg., Mailpoint 808, Southampton General Hospital, Tremona Rd., Southampton SO16 6YD, UK. Tel.: 44-23-8079-5040; Fax: 44-23-8079-4264; E-mail: k.piper{at}soton.ac.uk.

² Recipient of a UK Department of Health Clinician Scientist fellowship. Supported in part by the Juvenile Diabetes Research Foundation, the Wellcome Trust, and the Mason Medical Research Foundation. To whom correspondence may be addressed: Human Genetics Division, Duthie Bldg., Mailpoint 808, Southampton General Hospital, Tremona Rd., Southampton SO16 6YD, UK. Tel.: 44-23-8079-5040; Fax: 44-23-8079-4264; E-mail: n.a.hanley{at}soton.ac.uk.

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