Wang L G, Beklemisheva A, Liu X M, Ferrari A C, Feng J, Chiao J W
NYU Cancer Institute, New York University School of Medicine, Manhattan VA Medical Center, New York, New York 10010, USA.
Mol Carcinog. 2007 Jan;46(1):24-31. doi: 10.1002/mc.20258.
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.
前列腺癌的特征是π类谷胱甘肽S-转移酶基因(GSTP1)沉默,该基因编码一种解毒酶。由于启动子/5'-非翻译区(UTR)中CpG岛的异常甲基化,GSTP1沉默发生在绝大多数前列腺肿瘤和癌前病变中。它是一种病理标志物,可能是肿瘤发生时氧化损伤和炎症的潜在原因。因此,抑制异常的启动子甲基化可能是预防癌变的有效手段。包括苯乙基异硫氰酸酯(PEITC)在内的几种异硫氰酸酯天然存在于十字花科蔬菜中,可在培养的前列腺癌细胞和异种移植瘤中诱导生长停滞和凋亡。研究了PEITC重新激活GSTP1的作用。将前列腺癌LNCaP细胞暴露于PEITC可抑制组蛋白脱乙酰酶(HDACs)的活性和水平,并诱导染色质展开的选择性组蛋白乙酰化和甲基化。同时,PEITC使雄激素依赖性和非依赖性LNCaP癌细胞中的启动子去甲基化,并将未甲基化的GSTP1恢复到正常前列腺细胞中的水平,通过甲基化特异性PCR和焦磷酸测序进行定量。PEITC对DNA和染色质的双重作用比5'-氮杂-2'-脱氧胞苷、丁酸钠或曲古抑菌素A(TSA)更有效,并且可能去抑制基因转录上的甲基结合域(MBD)。PEITC介导的DNA与染色质之间在使GSTP1基因去甲基化和重新激活方面的相互作用,在前列腺癌发生过程中至关重要地失活,这突显了癌症化学预防的主要机制。因此,可以开发新的方法,使用异硫氰酸酯来预防和抑制恶性肿瘤。