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Bone. 2015 Apr;73:223-32. doi: 10.1016/j.bone.2014.12.063. Epub 2015 Jan 5.

Wnt inhibitory factor 1 (WIF1) is a marker of osteoblastic differentiation stage and is not silenced by DNA methylation in osteosarcoma.

Author information

1
Stem Cell Regulation Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia. Electronic address: ebaker@svi.edu.au.
2
Stem Cell Regulation Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia.
3
Stem Cell Regulation Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
4
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia; Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia.
5
Cancer Epigenetics, Garvan Institute of Medical Research, Darlinghurst, Australia.
6
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland.
7
Stem Cell Regulation Unit, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia. Electronic address: cwalkley@svi.edu.au.

Abstract

Wnt pathway targeting is of high clinical interest for treating bone loss disorders such as osteoporosis. These therapies inhibit the action of negative regulators of osteoblastic Wnt signaling. The report that Wnt inhibitory factor 1 (WIF1) was epigenetically silenced via promoter DNA methylation in osteosarcoma (OS) raised potential concerns for such treatment approaches. Here we confirm that Wif1 expression is frequently reduced in OS. However, we demonstrate that silencing is not driven by DNA methylation. Treatment of mouse and human OS cells showed that Wif1 expression was robustly induced by HDAC inhibition but not by methylation inhibition. Consistent with HDAC dependent silencing, the Wif1 locus in OS was characterized by low acetylation levels and a bivalent H3K4/H3K27-trimethylation state. Wif1 expression marked late stages of normal osteoblast maturation and stratified OS tumors based on differentiation stage across species. Culture of OS cells under differentiation inductive conditions increased expression of Wif1. Together these results demonstrate that Wif1 is not targeted for silencing by DNA methylation in OS. Instead, the reduced expression of Wif1 in OS cells is in context with their stage in differentiation.

KEYWORDS:

HDAC; Methylation; Osteoblast; Osteoporosis; Osteosarcoma; WIF1

PMID:
25571841
DOI:
10.1016/j.bone.2014.12.063
[Indexed for MEDLINE]

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