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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2015 May 19

PMID 25982816

Citations 111

Authors

Pierrick G J Fournier

Patricia Juarez

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

Affiliations

Soon will be listed here.

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.

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