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 Mohammad, Clark Wells, John Chirgwin, Theresa Guise

Research output: Contribution to journalArticle

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

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Transforming Growth Factors
Prostatic Neoplasms
Bone Neoplasms
Neoplasm Metastasis
Gene Expression
Bone and Bones
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Genes
Protein Isoforms
Up-Regulation
Breast Neoplasms
Membranes
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Fournier, P. G. J., Juárez, P., Jiang, G., Clines, G. A., Niewolna, M., Kim, H. S., ... Guise, T. (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

The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. / Fournier, Pierrick G J; Juárez, Patricia; Jiang, Guanglong; Clines, Gregory A.; Niewolna, Maria; Kim, Hun Soo; Walton, Holly W.; Peng, Xiang Hong; Liu, Yunlong; Mohammad, Khalid; Wells, Clark; Chirgwin, John; Guise, Theresa.

In: Cancer Cell, Vol. 27, No. 6, 08.06.2015, p. 809-821.

Research output: Contribution to journalArticle

Fournier, PGJ, Juárez, P, Jiang, G, Clines, GA, Niewolna, M, Kim, HS, Walton, HW, Peng, XH, Liu, Y, Mohammad, K, Wells, C, Chirgwin, J & Guise, T 2015, 'The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone', Cancer Cell, vol. 27, no. 6, pp. 809-821. https://doi.org/10.1016/j.ccell.2015.04.009
Fournier PGJ, Juárez P, Jiang G, Clines GA, Niewolna M, Kim HS et al. The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. Cancer Cell. 2015 Jun 8;27(6):809-821. https://doi.org/10.1016/j.ccell.2015.04.009
Fournier, Pierrick G J ; Juárez, Patricia ; Jiang, Guanglong ; Clines, Gregory A. ; Niewolna, Maria ; Kim, Hun Soo ; Walton, Holly W. ; Peng, Xiang Hong ; Liu, Yunlong ; Mohammad, Khalid ; Wells, Clark ; Chirgwin, John ; Guise, Theresa. / The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. In: Cancer Cell. 2015 ; Vol. 27, No. 6. pp. 809-821.
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