The transforming growth factor–β (TGF-β) signaling pathway regulates various physiological processes and has a complex role in cancer. Although TGF-β can suppress tumor growth in the early stages of cancer, it can promote tumor progression in the later stages. Fournier et al. found that a negative feedback regulator of the TGF-β pathway suppressed the metastasis of prostate cancer to bone. Microarray and promoter activity analysis in cultured PC-3 prostate cancer cells showed that TGF-β signaling induced various genes that are associated with multiple steps of the metastatic process, with PMEPA1 (encoding prostate transmembrane protein, androgen induced 1) exhibiting the greatest induction. Bioinformatics analysis of patient samples revealed that lower PMEPA1 expression in primary tumors correlated with increased incidence of recurrence in prostate cancer and breast cancer patients. Compared with normal prostate tissue, PMEPA1 expression was increased in primary prostate tumors but similar in bone metastases, indicating that metastatic progression correlates with a decrease in PMEPA1 expression. Knocking down PMEPA1 increased proliferation of PC-3 cells cultured with TGF-β and increased the number of resulting osteolytic lesions when these PMEPA1-knockdown cells were inoculated into mice. In COS7 cells cotransfected with SMADs or HECT E3 ligases, the membrane-bound isoform of PMEPA1 (but not other isoforms or mutants lacking certain motifs) coimmunoprecipitated with the TGF-β effectors SMAD2 and SMAD3, as well as the E3 ubiquitin ligase NEDD4-1, and enhanced the interaction between SMAD2 and the E3 ligase SMURF2. Curiously, neither a proteasome inhibitor nor expression of a catalytically inactive SMURF2 prevented the inhibitory effect of overexpressed PMEPA1 on TGF-β signaling activity. TGF-β exposure of PC-3 cells in which PMEPA1 was knocked down resulted in increased SMAD2 phosphorylation and increased the nuclear retention time of SMAD2, as well as increased expression of several TGF-β target genes, compared with the TGF-β–induced responses in control cells. The findings suggest that PMEPA1 facilitates the interaction of SMAD2 with E3 ligases to limit TGF-β signaling, perhaps independently of ubiquitin-mediated degradation. Loss of this negative regulation may enable the prometastatic effects of TGF-β cancer patients.
P. G. J. Fournier, P. Juárez, G. Jiang, G. A. Clines, M. Niewolna, H. S. Kim, H. W. Walton, X. H. Peng, Y. Liu, K. S. Mohammad, C. D. Wells, J. M. Chirgwin, T. A. Guise, The TGF-β signaling regulator PMEPA1 suppresses prostate cancer metastases to bone. Cancer Cell 27, 809–821 (2015). [PubMed]