title: MED12 overexpression is a frequent event in castration-resistant prostate cancer.
abstract: In a recent effort to unravel the molecular basis of prostate cancer (PCa), Barbieri and colleagues using whole-exome sequencing identified a novel recurrently mutated gene, MED12, in 5.4% of primary PCa. MED12, encoding a subunit of the Mediator complex, is a transducer of Wnt/β-catenin signaling, linked to modulation of hedgehog signaling and to the regulation of transforming growth factor beta (TGFβ)-receptor signaling. Therefore, these studies prompted us to investigate the relevance of MED12 in PCa. Expression of MED12, SMAD3 phosphorylation, and proliferation markers was assessed by immunohistochemistry on tissue microarrays from 633 patients. siRNA-mediated knockdown of MED12 was carried out on PCa cell lines followed by cellular proliferation assays, cell cycle analysis, apoptosis assays, and treatments with recombinant TGFβ3. We found nuclear overexpression of MED12 in 40% (28/70) of distant metastatic castration-resistant prostate cancer (CRPC(MET)) and 21% (19/90) of local-recurrent CRPC (CRPC(LOC)) in comparison with frequencies of less than 11% in androgen-sensitive PCa, and no overexpression in benign prostatic tissues. MED12 expression was significantly correlated with high proliferative activity in PCa tissues, whereas knockdown of MED12 decreased proliferation, reduced G1- to S-phase transition, and increased the expression of the cell cycle inhibitor p27. TGFβ signaling activation associates with MED12 nuclear overexpression in tissues and results in a strong increase in MED12 nuclear expression in cell lines. Furthermore, MED12 knockdown reduced the expression of the TGFβ target gene vimentin. Our findings show that MED12 nuclear overexpression is a frequent event in CRPC in comparison with androgen-sensitive PCa and is directly implicated in TGFβ signaling.
authors.forename: David
authors.initials: D
authors.lastname: Adler
authors.forename: Anne
authors.initials: A
authors.lastname: Offermann
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.forename: Roopika
authors.initials: R
authors.lastname: Menon
authors.forename: Isabella
authors.initials: I
authors.lastname: Syring
authors.forename: Michael
authors.initials: M
authors.lastname: Nowak
authors.forename: Rebecca
authors.initials: R
authors.lastname: Halbach
authors.forename: Wenzel
authors.initials: W
authors.lastname: Vogel
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
authors.forename: Tobias
authors.initials: T
authors.lastname: Zellweger
authors.forename: Cyrill A
authors.initials: CA
authors.lastname: Rentsch
authors.forename: Maria
authors.initials: M
authors.lastname: Svensson
authors.forename: Ove
authors.initials: O
authors.lastname: Andren
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D046888:Tissue Array Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta
keywords: MED12; castration-resistant; overexpression; prostate cancer