Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy lesions (PIA). GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However, GSTP1 methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns of GSTP1 promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree of GSTP1 methylation showed progression from PIA << PIN < CaP. PIN lesions showed more partial methylation compared to CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in the GSTP1 CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP.
Cancer prevention research (Philadelphia, Pa.). 2023 Jun 22 [Epub ahead of print]
Harshath Gupta, Hitoshi Inoue, Yasutomo Nakai, Masashi Nakayama, Tracy Jones, Jessica L Hicks, Balasubramanian Kumar, Meltem Gurel, William G Nelson, Angelo M De Marzo, Srinivasan Yegnasubramanian
Johns Hopkins University School of Medicine, Baltimore, MD, United States., Ikeda Municipal Hospital, Ikeda, Osaka, Japan., Osaka International Cancer Institute, Osaka, Osaka, Japan., Johns Hopkins University School of Medicine, Baltimore, United States., Independent Computer Scientist, Monte Sereno, CA, United States., BenevolentAI (United Kingdom), London, United Kingdom., Johns Hopkins University, Baltimore, MD, United States.