P38-regulated FOXC1 stability is required for colorectal cancer metastasis.

Abstract

Aberrant expression of forkhead box C1 (FOXC1) promotes tumor metastasis in multiple human malignant tumors. However, the upstream modulating mode and downstream molecular mechanism of FOXC1 in metastasis of colorectal cancer (CRC) remain unclear. Herein we describe a systematic analysis of FOXC1 expression and prognosis in CRC performed on our clinical data and public databases, which indicated that FOXC1 upregulation in CRC samples was significantly associated with poor prognosis. FOXC1 knockdown inhibited migration and invasion, whereas FOXC1 overexpression caused the opposite phenotype in vitro and in vivo. Furthermore, MMP10, SOX4 and SOX13 were verified as the target genes of FOXC1 for promoting CRC metastasis. MMP10 was demonstrated as the direct target and mediator of FOXC1. Interestingly, Ser241 and Ser272 of FOXC1 were identified as the key sites to interact with p38 and phosphorylation, which were critically required for maintaining the stability of FOXC1 protein. Moreover, FOXC1 was dephosphorylated by protein phosphatase 2A and phosphorylated by p38, which maintained FOXC1 protein stability through inhibiting ubiquitination. Expression of p38 was correlated with FOXC1 and MMP10 expression, indirectly indicating that FOXC1 was regulated by p38 MAPK. Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13; p38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. In conclusion, the protein stability of FOXC1 mediated by p38 contributes to the metastatic effect in CRC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.