title: The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone.
abstract: Transforming growth factor-β (TGF-β) regulates the expression of genes supporting breast cancer cells in bone, but little is known about prostate cancer bone metastases and TGF-β. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGF-β upregulates in prostate cancer cells a set of genes associated with cancer aggressiveness and bone metastases, and the most upregulated gene was PMEPA1. In patients, PMEPA1 expression decreased in metastatic prostate cancer and low Pmepa1 correlated with decreased metastasis-free survival. Only membrane-anchored isoforms of PMEPA1 interacted with R-SMADs and ubiquitin ligases, blocking TGF-β signaling independently of the proteasome. Interrupting this negative feedback loop by PMEPA1 knockdown increased prometastatic gene expression and bone metastases in a mouse prostate cancer model.
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Pierrick G J
authors.initials: PG
authors.lastname: Fournier
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Juárez
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Guanglong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Clines
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Niewolna
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hun Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Holly W
authors.initials: HW
authors.lastname: Walton
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Xiang Hong
authors.initials: XH
authors.lastname: Peng
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Clark D
authors.initials: CD
authors.lastname: Wells
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Chirgwin
authors.affiliation: Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA. Electronic address: tguise@iu.edu.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011621:Pteridines / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C412868:PMEPA1 protein, human; D011621:Pteridines; C511004:SD-208; D016212:Transforming Growth Factor beta