Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
Mol Carcinog. 2021 Jun;60(6):391-402. doi: 10.1002/mc.23299. Epub 2021 Apr 13.
Epigenetics/epigenomics has been shown to be involved in carcinogenesis. However, how the epigenome would be altered in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model and the effect of cancer chemopreventive phytochemical phenethyl isothiocyanate (PEITC) on the epigenome in TRAMP mice are not known. PEITC has been reported to reduce the risk of many cancers including prostate cancer (PCa). In this study, male TRAMP mice were fed a control diet or diet containing 0.05% PEITC from 8 weeks to 16 weeks. The tumor incidence was reduced in the PEITC diet (0/6) as compared with the control diet (6/7). RNA-sequencing (RNA-seq) analyses on nontumor and tumor prostatic tissues revealed several pathways like cell cycle/Cdc42 signaling, inflammation, and cancer-related signaling, were activated in prostate tissues of TRAMP mice but were reversed or attenuated in TRAMP mice fed with PEITC diet. DNA CpG methyl-seq analyses showed that global methylation patterns of prostate samples from TRAMP mice were hugely different from those of wild-type mice. Dietary PEITC partially reversed the global methylation changes during prostatic carcinogenesis. Integration of RNA-seq and DNA methyl-seq analyses identified a list of genes, including Adgrb1 and Ebf4, with an inverse regulatory relationship between their RNA expression and CpG methylation. In summary, our current study demonstrates that alteration of the global epigenome in TRAMP prostate tumor and PEITC administration suppresses PCa carcinogenesis, impacts global CpG epigenome and transcriptome, and attenuates carcinogenic pathways like cell cycle arrest and inflammation. These results may provide insights and epigenetic markers/targets for PCa prevention and treatment in human PCa patients.
表观遗传学/表观基因组学已被证明与致癌作用有关。然而，在转基因前列腺腺癌小鼠（TRAMP）癌症模型中，表观基因组如何发生改变，以及癌症化学预防植物化学物苯乙基异硫氰酸酯（PEITC）对 TRAMP 小鼠表观基因组的影响尚不清楚。已有报道称，PEITC 可降低包括前列腺癌（PCa）在内的多种癌症的风险。在这项研究中，雄性 TRAMP 小鼠从 8 周龄到 16 周龄喂食对照饮食或含 0.05%PEITC 的饮食。与对照饮食（6/7）相比，PEITC 饮食（0/6）中的肿瘤发生率降低。非肿瘤和肿瘤前列腺组织的 RNA 测序（RNA-seq）分析显示，细胞周期/Cdc42 信号、炎症和癌症相关信号等几种途径在 TRAMP 小鼠的前列腺组织中被激活，但在喂食 PEITC 饮食的 TRAMP 小鼠中被逆转或减弱。DNA CpG 甲基化-seq 分析表明，TRAMP 小鼠前列腺样本的整体甲基化模式与野生型小鼠有很大差异。饮食 PEITC 部分逆转了前列腺癌发生过程中的整体甲基化变化。RNA-seq 和 DNA 甲基化-seq 分析的整合确定了一组基因，包括 Adgrb1 和 Ebf4，它们的 RNA 表达和 CpG 甲基化之间存在反向调节关系。总之，我们目前的研究表明，TRAMP 前列腺肿瘤中全基因组表观基因组的改变和 PEITC 给药抑制了 PCa 的发生，影响了全基因组 CpG 表观基因组和转录组，并减弱了细胞周期停滞和炎症等致癌途径。这些结果可为人类 PCa 患者的 PCa 预防和治疗提供见解和表观遗传标记/靶点。
