title: MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer.
abstract: The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-β3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPC(MET) ) and 70% of local-recurrent CRPC (CRPC(LOC) ), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-β signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-β-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model.
authors.affiliation: Department of Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany; Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Adler
authors.forename: Roopika
authors.initials: R
authors.lastname: Menon
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.forename: Anne
authors.initials: A
authors.lastname: Offermann
authors.forename: Angela
authors.initials: A
authors.lastname: Queisser
authors.forename: Diana
authors.initials: D
authors.lastname: Boehm
authors.forename: Wenzel
authors.initials: W
authors.lastname: Vogel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Rüenauver
authors.forename: Christian
authors.initials: C
authors.lastname: Ruiz
authors.forename: Tobias
authors.initials: T
authors.lastname: Zellweger
authors.forename: Maria
authors.initials: M
authors.lastname: Svensson
authors.forename: Ove
authors.initials: O
authors.lastname: Andren
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wernert
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
mesh_terms: D000368:Aged; D000728:Androgens / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011758:Pyrroles; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C410798:AR protein, human; D000728:Androgens; D056892:Mediator Complex; D011758:Pyrroles; D011944:Receptors, Androgen; C065762:ST 679; D005998:Glycine
keywords: MED15; TGF-β; castration-resistant; prostate cancer