The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone

Pierrick G.J. Fournier, Patricia Juárez, Guanglong Jiang, Gregory A. Clines, Maria Niewolna, Hun Soo Kim, Holly W. Walton, Xiang Hong Peng, Yunlong Liu, Khalid S. Mohammad, Clark D. Wells, John M. Chirgwin, Theresa A. Guise

Research output: Contribution to journalArticle

101 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)809-821
Number of pages13
JournalCancer Cell
Volume27
Issue number6
DOIs
StatePublished - Jun 8 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Fournier, P. G. J., Juárez, P., Jiang, G., Clines, G. A., Niewolna, M., Kim, H. S., Walton, H. W., Peng, X. H., Liu, Y., Mohammad, K. S., Wells, C. D., Chirgwin, J. M., & Guise, T. A. (2015). The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. Cancer Cell, 27(6), 809-821. https://doi.org/10.1016/j.ccell.2015.04.009