Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and
cancer. NF-κB has a role in
tumorigenesis and
tumor growth, as well as promotion of
metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at
serine residues S536 and S276, is critical for RelA function.
Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that
phosphatases targeting RelA could have
tumor-inhibiting activities; however, few RelA
phosphatases have been identified. Here, we identified
tumor inhibitory and RelA
phosphatase activities of the
protein phosphatase 2C (PP2C)
phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of
monocyte chemotactic protein-1/
chemokine (C-C motif) ligand 2 and
interleukin-6,
cytokines implicated in
cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic
prostate cancer deposits had lower PPM1A expression compared with primary
tumors without distant
metastases. A hematogenous
metastasis mouse model revealed that PPM1A expression inhibited bony
metastases of
prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA
phosphatase that regulates NF-κB activity and that PPM1A has
tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits
prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in
tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony
metastases in human
cancer.