title: ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity.
abstract: MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.
authors.affiliation: Department of Physiology and Biophysics, Robert Wood Johnson Medical School, UMDNJ, 683 Hoes Lane, Piscataway, New Jersey 08854, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Shazia
authors.initials: S
authors.lastname: Irshad
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Madesh
authors.initials: M
authors.lastname: Belakavadi
authors.forename: Marina
authors.initials: M
authors.lastname: Chekmareva
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Fondell
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C538855:MED1 protein, human; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; C102837:Nkx3-1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
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