Methylation of the PMEPA1 gene, a negative regulator of the androgen receptor in prostate cancer.
The prostate transmembrane protein androgen induced 1 (PMEPA1) gene is highly expressed in prostate epithelial cells and is a direct transcriptional target for the androgen receptor (AR). AR protein levels are controlled by the AR-PMEPA1 negative feedback loop through NEDD4-E3 ligase. Reduced expression of PMEPA1 observed in prostate tumors, suggests that loss of PMEPA1 may play critical roles in prostate tumorigenesis. This study focuses on epigenetic mechanisms of reduced PMEPA1 expression in the cancer of the prostate (CaP). Benign (n = 77) and matched malignant (n = 77) prostate epithelial cells were laser capture micro-dissected from optimum cutting temperature embedded frozen prostate sections from 42 Caucasian American (CA) and 35 African American (AA) cases. Purified DNA specimens were analyzed for CpG methylation of the PMEPA1 gene. PMEPA1 mRNA expression levels were evaluated by qRT-PCR. Analysis of PMEPA1 methylation and mRNA expression in the same tumor cell populations indicated a significant inverse correlation between mRNA expression and methylation in CaP (P = 0.0115). We noted higher frequency of CpG methylation within the evaluated first intronic region of the PMEPA1 gene in prostate tumors of CA men as compared with AA. In CaP cell lines, PMEPA1 expression was induced and AR protein levels were diminished in response to treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (decitabine). Cell culture-based studies demonstrated that decitabine restores PMEPA1 expression in AR-positive CaP cell lines. This report reveals the potential role of PMEPA1 gene methylation in the regulation of AR stability. Thus, downregulation of PMEPA1 may result in increased AR protein levels and function in CaP cells, contributing to prostate tumorigenesis.
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Shashwat
S
Sharad
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Lakshmi
L
Ravindranath
Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
Michael C
MC
Haffner
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Hua
H
Li
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Wusheng
W
Yan
The Joint Pathology Center; Silver Spring, MD USA.
Isabell A
IA
Sesterhenn
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Yongmei
Y
Chen
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA; Urology Service; Walter Reed National Military Medical Center; Bethesda, MD USA.
Amina
A
Ali
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Alagarsamy
A
Srinivasan
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA; Urology Service; Walter Reed National Military Medical Center; Bethesda, MD USA.
David G
DG
McLeod
Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
Srinivasan
S
Yegnasubramanian
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Shiv
S
Srivastava
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Albert
A
Dobi
Center for Prostate Disease Research; Department of Surgery; Uniformed Services University of the Health Sciences; Bethesda, MD USA.
Gyorgy
G
Petrovics
D001741:Black or African American; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D015870:Gene Expression; D006801:Humans; D007438:Introns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D044465:White People
D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; C412868:PMEPA1 protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen; D000077209:Decitabine; D001374:Azacitidine
PMEPA1; androgen receptor; laser capture microdissection; methylation; prostate cancer; tumor suppressor