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.

中文翻译：

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异硫氰酸苯乙酯对 TRAMP 小鼠的 DNA 甲基化组、转录组和前列腺癌预防作用


表观遗传学/表观基因组学已被证明与癌发生有关。然而，转基因小鼠前列腺癌 (TRAMP) 癌症模型中的表观基因组如何改变以及癌症化学预防植物化学物质异硫氰酸苯乙酯 (PEITC) 对 TRAMP 小鼠表观基因组的影响尚不清楚。据报道，PEITC 可以降低多种癌症的风险，包括前列腺癌 (PCa)。在这项研究中，雄性 TRAMP 小鼠在 8 周至 16 周期间被喂食对照饮食或含有 0.05% PEITC 的饮食。与对照饮食 (6/7) 相比，PEITC 饮食 (0/6) 的肿瘤发生率降低。对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 信号传导、炎症和癌症相关信号传导等多种途径在 TRAMP 小鼠的前列腺组织中被激活，但在喂食的 TRAMP 小鼠中被逆转或减弱与 PEITC 饮食。 DNA CpG 甲基化序列分析表明，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不同。膳食 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-seq 分析的整合确定了一系列基因，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 前列腺肿瘤和 PEITC 给药中整体表观基因组的改变可抑制 PCa 癌变，影响整体 CpG 表观基因组和转录组，并减弱细胞周期停滞和炎症等致癌途径。这些结果可能为人类前列腺癌患者的前列腺癌预防和治疗提供见解和表观遗传标记/靶点。