Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts

• Published in: Human genetics Vol. 131; no. 9; pp. 1453 - 1466
• Main Authors: Lou, Hong, Li, Hongchuan, Yeager, Meredith, Im, Kate, Gold, Bert, Schneider, Thomas D., Fraumeni, Joseph F., Chanock, Stephen J., Anderson, Stephen K., Dean, Michael
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-09-2012; Springer; Springer Nature B.V
• Subjects: 5' Untranslated Regions; Androgen receptors; Androgens; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer research; Cell Line, Tumor; Codons; Computer applications; Data processing; Epigenetic inheritance; epigenetics; Epithelial cells; Exons; Fusion protein; Gene deletion; Gene Function; Gene Fusion; Genes; Genetic aspects; Genetic research; Genomes; Genomics; Health aspects; Human Genetics; Humans; Immunoglobulins; Immunology; Luciferase; Male; Medical research; Metabolic Diseases; Molecular Medicine; Nuclear Receptor Coactivators - genetics; Original Investigation; Promoter Regions, Genetic; Promoters; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Secretory Proteins - genetics; Proteins; Real-Time Polymerase Chain Reaction; Regulatory sequences; Regulatory Sequences, Nucleic Acid; RNA; RNA, Messenger - genetics; Sarcoma; Semen; Signal transduction; Splicing; Transcription; Transfection; United States > US; Androgen Receptor; Fusion Transcript; LNCaP Cell; Prostate Cancer Cell Line; DU145 Cell
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-012-1182-2

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.