title: RETRACTED: The transcription factor FOXF1 promotes prostate cancer by stimulating the mitogen-activated protein kinase ERK5.
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.
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Fulford
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Milewski
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ustiyan
authors.affiliation: Department of Biomedical, Chemical, and Environmental Engineering, University of Cincinnati College of Engineering and Applied Science, Cincinnati, OH 45221, USA.
authors.forename: Navin
authors.initials: N
authors.lastname: Ravishankar
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Tien
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Sreeharsha
authors.initials: S
authors.lastname: Masineni
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. tatiana.kalin@cchmc.org.
authors.forename: Tanya V
authors.initials: TV
authors.lastname: Kalin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1 / Q000378:metabolism
chemical_list: C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse; D048054:Mitogen-Activated Protein Kinase 7; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482618:MAP3K2 protein, human; C482619:Map3k2 protein, mouse