Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer.

Prostate carcinoma is characterized by the silencing of pi-class glutathione S-transferase gene (GSTP1), which encodes a detoxifying enzyme. The silencing of GSTP1, due to aberrant methylation at the CpG island in the promoter/5'-UTR, occurs in the vast majority of prostate tumors and precancerous lesions. It is a pathologic marker and probably an underlying cause of oxidative damage and inflammation at tumor initiation. Inhibition of the aberrant promoter methylation could therefore be an effective mean to prevent carcinogenesis. Several isothiocyanates, including phenethyl isothiocyanate (PEITC), found naturally in cruciferous vegetables, induced growth arrest and apoptosis in prostate cancer cells in culture and xenografts. The effects of PEITC to reactivate GSTP1 were investigated. Exposure of prostate cancer LNCaP cells to PEITC inhibited the activity and level of histone deacetylases (HDACs), and induced selective histone acetylation and methylation for chromatin unfolding. Concurrently PEITC demethylated the promoter and restored the unmethylated GSTP1 in both androgen-dependent and -independent LNCaP cancer cells to the level found in normal prostatic cells, as quantified by methylation-specific PCR and pyrosequencing. The dual action of PEITC on both the DNA and chromatin was more effective than 5'-Aza-2'-deoxycytidine, sodium butyrate, or trichostatin A (TSA), and may de-repress the methyl-binding domain (MBD) on gene transcription. The PEITC-mediated cross-talk between the DNA and chromatin in demethylating and reactivating GSTP1 genes, which is critically inactivated in prostate carcinogenesis, underlines a primary mechanism of cancer chemoprevention. Consequently, new approaches could be developed, with isothiocyanates to prevent and inhibit malignancies.

Wang LG ，Beklemisheva A ，Liu XM ，Ferrari AC ，Feng J ，Chiao JW ... -  《MOLECULAR CARCINOGENESIS》

Reversal of GSTP1 CpG island hypermethylation and reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer cells by treatment with procainamide.

Lin X ，Asgari K ，Putzi MJ ，Gage WR ，Yu X ，Cornblatt BS ，Kumar A ，Piantadosi S ，DeWeese TL ，De Marzo AM ，Nelson WG ... -  《CANCER RESEARCH》

De-repression of the p21 promoter in prostate cancer cells by an isothiocyanate via inhibition of HDACs and c-Myc.

Wang LG ，Liu XM ，Fang Y ，Dai W ，Chiao FB ，Puccio GM ，Feng J ，Liu D ，Chiao JW ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》

Cytosine methylation represses glutathione S-transferase P1 (GSTP1) gene expression in human prostate cancer cells.

Singal R ，van Wert J ，Bashambu M 《CANCER RESEARCH》

Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells.

Stirzaker C ，Song JZ ，Davidson B ，Clark SJ ... -  《CANCER RESEARCH》