A role for DNA methylation in regulating the growth suppressor PMEPA1 gene in prostate cancer.
A cascade of epigenetic events contributes to the selective growth advantage of cancer cells during tumor progression. PMEPA1 gene is an androgen-inducible negative regulator of cell growth in the prostate epithelium. During prostate cancer progression PMEPA1 gene transcription is reduced or lost prompting us to investigate the role of epigenetic events in this process. In LAPC4 cells harboring wild type androgen receptor decitabine (5-aza-2'-deoxycitidine) treatment resulted in increased expression of PMEPA1 along with other androgen-inducible genes, suggesting a role for DNA methylation in the repression of androgenic cell growth control signals in prostate cancer. In contrast, mutant androgen receptor expressing LNCaP cells were deficient in this response. Therefore, decitabine-induced expression of cell growth controlling genes such as NKX3.1 or PMEPA1 underlines the clinical applicability of decitabine in prostate tumors harboring wild type androgen receptor. Further analysis of DNA methylation within the PMEPA1 promoter downstream sequences suggests that methylation of SP1 binding sites may also contribute to the repression of PMEPA1 gene.
Richter
Eric
E
Center for Prostate Disease Research, Department of Surgery, US Military Cancer Institute, Uniformed Services University, Rockville, Maryland 20852, USA.
Masuda
Katsuaki
K
Cook
Christopher
C
Ehrich
Mathias
M
Tadese
Atekelt Y
AY
Li
Hongyun
H
Owusu
Anthony
A
Srivastava
Shiv
S
Dobi
Albert
A
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011944:Receptors, Androgen / Q000502:physiology; D016329:Sp1 Transcription Factor
D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; C412868:PMEPA1 protein, human; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; D000077209:Decitabine; D001374:Azacitidine