PMID- 24374838
OWN - NLM
STAT- MEDLINE
DCOM- 20140602
LR  - 20220329
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 135
IP  - 1
DP  - 2014 Jul 1
TI  - MED15, encoding a subunit of the mediator complex, is overexpressed at high 
      frequency in castration-resistant prostate cancer.
PG  - 19-26
LID - 10.1002/ijc.28647 [doi]
AB  - 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-beta3. 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-beta 
      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-beta-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.
CI  - (c) 2013 UICC.
FAU - Adler, David
AU  - Adler D
AD  - Department of Prostate Cancer Research, University Hospital of Bonn, Bonn, 
      Germany; Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
FAU - Menon, Roopika
AU  - Menon R
FAU - Braun, Martin
AU  - Braun M
FAU - Offermann, Anne
AU  - Offermann A
FAU - Queisser, Angela
AU  - Queisser A
FAU - Boehm, Diana
AU  - Boehm D
FAU - Vogel, Wenzel
AU  - Vogel W
FAU - Ruenauver, Kerstin
AU  - Ruenauver K
FAU - Ruiz, Christian
AU  - Ruiz C
FAU - Zellweger, Tobias
AU  - Zellweger T
FAU - Svensson, Maria
AU  - Svensson M
FAU - Andren, Ove
AU  - Andren O
FAU - Kristiansen, Glen
AU  - Kristiansen G
FAU - Wernert, Nicolas
AU  - Wernert N
FAU - Bubendorf, Lukas
AU  - Bubendorf L
FAU - Kirfel, Jutta
AU  - Kirfel J
FAU - Biskup, Saskia
AU  - Biskup S
FAU - Perner, Sven
AU  - Perner S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131209
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (AR protein, human)
RN  - 0 (Androgens)
RN  - 0 (Mediator Complex)
RN  - 0 (Pyrroles)
RN  - 0 (Receptors, Androgen)
RN  - 104076-16-6 (ST 679)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Aged
MH  - Androgens/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Gene Expression Regulation, Neoplastic
MH  - Glycine/*analogs & derivatives/biosynthesis/genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Mediator Complex/genetics/metabolism
MH  - Middle Aged
MH  - Prostatic Neoplasms, Castration-Resistant/*genetics/pathology
MH  - Pyrroles
MH  - Receptors, Androgen/genetics/metabolism
MH  - Signal Transduction/*genetics
OTO - NOTNLM
OT  - MED15
OT  - TGF-beta
OT  - castration-resistant
OT  - prostate cancer
EDAT- 2014/01/01 06:00
MHDA- 2014/06/03 06:00
CRDT- 2013/12/31 06:00
PHST- 2013/06/18 00:00 [received]
PHST- 2013/11/13 00:00 [revised]
PHST- 2013/11/18 00:00 [accepted]
PHST- 2013/12/31 06:00 [entrez]
PHST- 2014/01/01 06:00 [pubmed]
PHST- 2014/06/03 06:00 [medline]
AID - 10.1002/ijc.28647 [doi]
PST - ppublish
SO  - Int J Cancer. 2014 Jul 1;135(1):19-26. doi: 10.1002/ijc.28647. Epub 2013 Dec 9.