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.

Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

“…In these studies, overexpression led to the development of an increased number of metastatic lesions in preclinical animal models. Conversely, siRNA-mediated knockdown of FOXC1 practically abolished metastatic propensity (49,54,85) in most of these models, confirming the critical dependence of these cancers on FOXC1 to drive the metastatic program.…”

“…Amongst the gastrointestinal cancers, the evidence in support of the prognostic utility of FOXC1 is perhaps most robust in colon cancer. Three independent studies have confirmed the fact that FOXC1 expression status can in fact predict worse overall survival in colon cancer (47)(48)(49). One of these studies reports convincing data with regard to both overall survival and disease-free survival (48).…”

“…Aberrant expression of FOXC1 and activation of the FOXC1-p38-MAPK loop promotes tumor metastasis in colorectal cancer (CRC) (49). IGF-1R and FOXC1 regulate each other in pancreatic cancer and FOXC1 is a direct downstream signaling molecule of IGF-1/IGF-1R axis.…”

FOXC1 Downregulates Nanog Expression by Recruiting HDAC2 to Its Promoter in F9 Cells Treated by Retinoic Acid

“…FOXC1 affects gene expression by binding their promoters or cooperating with other factors, and it also participates in signal transduction by working as a substrate of ERK1/2 to be phosphorylated at S272, which could increase its stability by reducing the proteasomal degradation of FOXC1 [75][76][77]. Though Functions of FOXC1 in signal transduction have been well-studied [78][79][80][81], our data suggest that FOXC1 may play unrevealed roles in the epigenetic regulation of gene expression. As seen in Figure 4h, the proteins DNMT1, HDAC2, RBBP4, Yy1, EP300, Trim28, and Smarca1/4/5 are involved in chromatin modification, regulation of chromosomal remodeling and gene expression.…”

Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer

“…The data accumulated over the years demonstrate the unique behavior of FOXC1 in cancer, particularly in basal-like breast cancer (BLBC) (Wang et al, 2018a). Other studies determined that FOXC1 is significantly involved in breast cancer (BRCA) (Sabapathi et al, 2019) and also colon adenocarcinoma (COAD) (Zhang et al, 2020), pancreatic adenocarcinoma (PAAD) (Subramani et al, 2018), and non-small-cell lung cancer (NSCLC) (Chen et al, 2016). Using genetic epistasis analysis, Liu found that FOXC1 attaches to integrin α7 (ITGA7) and FGFR4 and then activates their expression in metastatic colorectal cancer (CRC).…”