Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts.
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5'UTR and exons 1-2 of the MSMB pre-mRNA, with exons 2-10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between -27 and -236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.
Human Genetics Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Hong
H
Lou
Molecular Immunology Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Hongchuan
H
Li
Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Meredith
M
Yeager
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Kate
K
Im
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Bert
B
Gold
Gene Regulation and Chromosome Biology Laboratory, Molecular Information Theory Group, Frederick, MD 21702, USA.
Thomas D
TD
Schneider
Division of Cancer Epidemiology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Joseph F
JF
Fraumeni
Division of Cancer Epidemiology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Stephen J
SJ
Chanock
Molecular Immunology Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Stephen K
SK
Anderson
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Michael
M
Dean
D045744:Cell Line, Tumor; D050939:Gene Fusion; D006801:Humans; D008297:Male; D056918:Nuclear Receptor Coactivators / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*; D029584:Prostatic Secretory Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid
C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D029584:Prostatic Secretory Proteins; D012333:RNA, Messenger; C043076:beta-microseminoprotein