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

Cancer Cell. 2015 Jun 8;27(6):809-21. doi: 10.1016/j.ccell.2015.04.009. Epub 2015 May 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / prevention & control
  • Bone Neoplasms / secondary*
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Pteridines / pharmacology
  • Signal Transduction
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*


  • Membrane Proteins
  • PMEPA1 protein, human
  • Pteridines
  • SD-208
  • Transforming Growth Factor beta

Associated data

  • GEO/GSE58698