ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity.

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.

Jin F ，Irshad S ，Yu W ，Belakavadi M ，Chekmareva M ，Ittmann MM ，Abate-Shen C ，Fondell JD ... -  《-》

Loss of Nkx3.1 leads to the activation of discrete downstream target genes during prostate tumorigenesis.

Song H ，Zhang B ，Watson MA ，Humphrey PA ，Lim H ，Milbrandt J ... -  《-》

A coregulatory role for the mediator complex in prostate cancer cell proliferation and gene expression.

Vijayvargia R ，May MS ，Fondell JD 《CANCER RESEARCH》

RAMP1 is a direct NKX3.1 target gene up-regulated in prostate cancer that promotes tumorigenesis.

The homeodomain-containing transcription factor, NKX3.1, plays an important role in the suppression of prostate tumorigenesis. Herein, we identify the receptor activity-modifying protein 1 (RAMP1) as a direct NKX3.1 target gene through analysis of chromatin immunoprecipitation coupled to massively parallel sequencing and gene expression data. RAMP1 is a coreceptor for certain G-protein-coupled receptors, such as the calcitonin gene-related peptide receptor, to the plasma membrane. We found that RAMP1 expression is specifically elevated in human prostate cancer relative to other tumor types. Furthermore, RAMP1 mRNA and protein levels are significantly higher in human prostate cancer compared with benign glands. We identified multiple NKX3.1 binding sites in the RAMP1 locus in human prostate cancer cells and in the normal mouse prostate. Analyses of Nkx3.1 knockout mice and human prostate cancer cell lines indicate that NKX3.1 represses RAMP1 expression. Knockdown of RAMP1 by shRNA decreased prostate cancer cell proliferation and tumorigenicity in vitro and in vivo. By using gene expression profiling and pathway analyses, we identified several cancer-related pathways that are significantly altered in RAMP1 knockdown cells, including the mitogen-activated protein kinase signaling pathway. Further experiments confirmed a reduction in MAP2KI (MEK1) expression and phosphorylated-extracellular signal-regulated kinase 1/2 levels in RAMP1 knockdown cells. These data provide novel insights into the role of RAMP1 in promoting prostate tumorigenesis and support the potential of RAMP1 as a novel biomarker and possible therapeutic target in prostate cancer.

Logan M ，Anderson PD ，Saab ST ，Hameed O ，Abdulkadir SA ... -  《-》

Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth.

Chen Z ，Zhang C ，Wu D ，Chen H ，Rorick A ，Zhang X ，Wang Q ... -  《-》