Abstract
PMEPA1 is induced by TGFβ and inhibits TGFβ signaling to suppress prostate cancer bone metastasis.
Major finding: PMEPA1 is induced by TGFβ and inhibits TGFβ signaling to suppress prostate cancer bone metastasis.
Clinical relevance: Low PMEPA1 expression is associated with poor prognosis in breast and prostate cancers.
Impact: TGFβ inhibitors may effectively treat or prevent bone metastasis in prostate cancer.
Bone metastases occur in most patients with advanced prostate cancer and are incurable. However, little is known about the molecular pathways regulating metastatic spread to bone. TGFβ has been implicated in the development of bone metastases in breast cancer and melanoma, and is abundantly expressed in bone and released during osteoclastic bone resorption, prompting Fournier and colleagues to assess its role in prostate cancer bone metastasis. Treatment with a TGFβ receptor 1 inhibitor, SD208, significantly reduced prostate cancer bone metastasis and improved survival in mice. Gene expression analysis of prostate cancer cells revealed that TGFβ stimulated the expression of many genes involved in bone metastasis; the most highly upregulated of these genes was prostate transmembrane protein androgen induced 1 (PMEPA1), which was transcriptionally induced by TGFβ. Membrane-bound PMEPA1 inhibited TGFβ signaling by promoting the interaction of SMAD2 and SMAD3 with HECT E3 ubiquitin ligases independent of ubiquitination and proteasome degradation, supporting the role of PMEPA1 as a negative feedback regulator of TGFβ. PMEPA1 knockdown increased TGFβ signaling and expression of prometastatic TGFβ target genes in vitro and enhanced prostate cancer bone metastases in mice, suggesting that loss of PMEPA1 promotes metastatic spread to bone. Consistent with these findings, PMEPA1 expression was significantly increased in the primary tumors of patients with prostate, breast, or lung cancer, compared with normal tissue and distant metastases. In addition, low PMEPA1 expression in primary tumors correlated with increased tumor recurrence and decreased metastasis-free survival in prostate and breast cancers. These results suggest that TGFβ inhibition or enhanced activation of membrane-bound PMEPA1 may represent a strategy to treat or prevent prostate cancer bone metastasis, and suggest PMEPA1 as a potential prognostic marker for bone metastases.
