Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer
- 22 January 2008
- journal article
- research article
- Published by Wiley in The Prostate
- Vol. 68 (6), 661-674
- https://doi.org/10.1002/pros.20730
Abstract
BACKGROUND Transforming growth factor‐β (TGF‐β) is a potent growth inhibitor in a wide range of cell types. A transducer of TGF‐β signaling known as Mothers against decapentaplegic homologue 4 (Smad4) is a known tumor suppressor found on chromosome 18q21.1 and is typically inactivated by deletion or mutation in pancreatic and colorectal cancers. The purpose of the article is to investigate Smad4 expression, gene copy number and methylation status in advanced cases of prostate cancer. METHODS We have employed Methylation Specific PCR (MSP) to identify methylation sites within the Smad4 promoter and combined this with quantitative real‐time PCR to look for correlates between methylation status and Smad4 expression and to examine androgen receptor (AR) expression. Bacterial artificial chromosome–comparative genomic hybridization (BAC–CGH) has been used to look for genomic amplifications and deletions which may also contribute to expression changes. RESULTS We fail to find evidence of genomic deletions or amplifications affecting the Smad4 locus on chromosome 18 but show a correlation between promoter methylation and the loss of Smad4 expression in the same material. We confirm that the AR locus on the X chromosome is amplified in 30% of the advanced clinical samples and that this correlates with increased transcript levels as previously reported by other groups. CONCLUSION This indicates that epigenetic changes affect the expression of the Smad4 protein in prostate cancer and points to methylation of the promoter as a novel marker of and contributor to the disease warranting further study. Prostate 68: 661–674, 2008.Keywords
This publication has 33 references indexed in Scilit:
- The Loss of TGF-β Signaling Promotes Prostate Cancer MetastasisNeoplasia, 2003
- TGF-β signaling: positive and negative effects on tumorigenesisCurrent Opinion in Genetics & Development, 2002
- Role of transforming growth factor-?1 in prostate cancerMicroscopy Research and Technique, 2001
- Role of Transforming Growth Factor β in Human DiseaseNew England Journal of Medicine, 2000
- Transforming Growth Factor-ß1 and Prostate CancerScandinavian Journal of Urology and Nephrology, 2000
- Early castration-induced upregulation of transforming growth factor ?1 and its receptors is associated with tumor cell apoptosis and a major decline in serum prostate-specific antigen in prostate cancer patientsThe Prostate, 1999
- Transcriptional Activators of TGF-β Responses: SmadsCell, 1998
- TGF-β SIGNAL TRANSDUCTIONAnnual Review of Biochemistry, 1998
- DPC4 , A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1Science, 1996
- Inactivation of the Type II TGF-β Receptor in Colon Cancer Cells with Microsatellite InstabilityScience, 1995