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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 (CRPCMET) and 70% of local-recurrent CRPC (CRPCLOC), 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. What's new? MED15, a subunit of the Mediator transcriptional regulator complex, has been implicated in castration-resistant prostate cancer (CRPC). This study shows that 70 percent of local-recurrent CRPCs and 76 percent of distant metastatic CRPCs overexpress MED15 and that MED15 overexpression defines a highly lethal phenotype. MED15 expression was found to be increased by TGF-ß activation, such that MED15 knockdown affected TGF-β signaling and TGF-β-enhanced proliferation. Knockdown also resulted in decreased androgen-dependent and -independent proliferative activity. The findings, taken together with the evolutionary conservation of MED15, suggest that MED15 in CRPC may be a model of therapeutic-resistant disease.
Originalsprache | Englisch |
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Zeitschrift | International Journal of Cancer |
Jahrgang | 135 |
Ausgabenummer | 1 |
Seiten (von - bis) | 19-26 |
Seitenumfang | 8 |
ISSN | 0020-7136 |
DOIs | |
Publikationsstatus | Veröffentlicht - 01.07.2014 |
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Emmy Noether-Nachwuchsgruppe: TMPRSS2-ERG Genfusion als neuer Biomarker für Prostatakarzinom-Patienten und Entwicklung eines Urin-Tests zur nicht-invasiven Diagnostik des Prostatakarzinoms mit Genfusion
Perner, S. (Projektleiter*in (PI))
01.01.07 → 31.12.13
Projekt: DFG-Projekte › DFG-Stipendien: Emmy Noether-Programm