Research ArticleCancer

The transcription factor FOXF1 promotes prostate cancer by stimulating the mitogen-activated protein kinase ERK5

Sci. Signal.  10 May 2016:
Vol. 9, Issue 427, pp. ra48
DOI: 10.1126/scisignal.aad5582

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Out-FOXing prostate cancer

Some types of prostate cancer can be aggressive, and these metastatic forms of the disease have few treatment options. Fulford et al. found that prostate tumors from some patients express the gene encoding the transcription factor forkhead box F1 (FOXF1), which is not expressed in normal prostate epithelium. Overexpressing FOXF1 increased tumor growth and metastatic progression when tumor cells were implanted into mice. FOXF1 bound to and increased the expression of genes encoding the kinase ERK5 and two upstream kinases, MAP3K2 and WNK1. Pharmacologically inhibiting ERK5 or knocking down FOXF1, ERK5, or both MAP3K2 and WNK1 suppressed prostate tumor growth and metastasis. The findings indicate targets for personalizing therapeutic intervention in prostate cancer patients with FOXF1-positive tumors.

Abstract

Forkhead box F1 (FOXF1) is a stromal transcription factor that is not expressed in epithelial cells of normal prostate tissue. The role of FOXF1 in cancer is conflicting; its loss in some cancers suggests a tumor suppressive function, but its abundance in others is associated with protumorigenic and metastatic traits. Extracellular signal–regulated kinase 5 (ERK5) is associated with advanced-stage prostate adenocarcinoma (PCa) in patients. We detected a population of FOXF1-positive tumor cells in aggressive mouse and human PCa. Using two murine orthotopic models of PCa, we found that overexpression of FOXF1 in Myc-CaP and TRAMP prostate tumor cells induced tumor growth in the prostate and progression to peritoneal metastasis. Increased growth of FOXF1-positive prostate tumors was associated with increased phosphorylation of ERK5, a member of the mitogen-activated protein kinase (MAPK) family. FOXF1 transcriptionally induced and directly bound to promoter regions of genes encoding the kinases MAP3K2 and WNK1, which promoted the phosphorylation and activation of ERK5. Knockdown of ERK5 or both MAP3K2 and WNK1 in FOXF1-overexpressing PCa cells reduced cell proliferation in culture and suppressed tumor growth and tumor metastasis when implanted into mice. In human tumors, FOXF1 expression correlated positively with that of MAP3K2 and WNK1. Thus, in contrast to some tumors where FOXF1 may function as a tumor suppressor, FOXF1 promotes prostate tumor growth and progression by activating ERK5 signaling. Our results also indicate that ERK5 may be a new therapeutic target in patients with FOXF1-positive PCa.

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