title: Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-β/SMAD3 autocrine loop.
abstract: Abnormal stem cell function makes a known contribution to many malignant tumors, but the role of stem cells in benign tumors is not well understood. Here, we show that ossifying fibroma (OF) contains a stem cell population that resembles mesenchymal stem cells (OFMSCs) and is capable of generating OF-like tumor xenografts. Mechanistically, OFMSCs show enhanced TGF-β signaling that induces aberrant proliferation and deficient osteogenesis via Notch and BMP signaling pathways, respectively. The elevated TGF-β activity is tightly regulated by JHDM1D-mediated epigenetic regulation of thrombospondin-1 (TSP1), forming a JHDM1D/TSP1/TGF-β/SMAD3 autocrine loop. Inhibition of TGF-β signaling in OFMSCs can rescue their abnormal osteogenic differentiation and elevated proliferation rate. Furthermore, chronic activation of TGF-β can convert normal MSCs into OF-like MSCs via establishment of this JHDM1D/TSP1/TGF-β/SMAD3 autocrine loop. These results reveal that epigenetic regulation of TGF-β signaling in MSCs governs the benign tumor phenotype in OF and highlight TGF-β signaling as a candidate therapeutic target.
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.forename: Cunye
authors.initials: C
authors.lastname: Qu
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamaza
authors.forename: Ruili
authors.initials: R
authors.lastname: Yang
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Duan
authors.forename: Kentaro
authors.initials: K
authors.lastname: Akiyama
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Qunzhou
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.forename: Yibu
authors.initials: Y
authors.lastname: Chen
authors.forename: Hank Heng
authors.initials: HH
authors.lastname: Qi
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D018214:Fibroma, Ossifying / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C481348:SPZ1 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta