Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Horm Metab Res. 2012 Jun;44(7):511-9. doi: 10.1055/s-0032-1311566. Epub 2012 Apr 11.
The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes ("methylome") in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i. e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease.
胰岛素样生长因子-I（IGF-IR）和雄激素（AR）受体是前列腺癌的重要角色。IGF-I 和雄激素信号通路之间的功能相互作用在前列腺癌从早期到晚期的进展中起着至关重要的作用。DNA 甲基化是影响基因表达的主要表观遗传改变。肿瘤抑制基因启动子的高甲基化是人类癌症中的一个常见事件，导致特定基因的失活和抑制。本研究的目的是在复制前列腺癌进展的细胞模型中鉴定出整套甲基化基因（“甲基组”）。通过用去甲基化剂 5-氮杂-2'-脱氧胞苷（5-Aza）处理细胞，然后进行 DNA 微阵列分析，建立了 P69（早期、良性）和 M12（晚期、转移性）前列腺癌细胞系的甲基化谱。对 5-Aza 处理和未处理细胞的全基因组比较甲基化分析鉴定了在 P69 中过表达的 297 个基因和在 M12 细胞中过表达的 191 个基因。有 102 个基因在良性和转移性细胞系中均上调。此外，我们的分析还确定了 PITX2 基因作为 AR 和 IGF-IR 基因上游的主调控因子。PITX2 启动子在 P69 细胞中呈半甲基化，但在 M12 细胞中完全甲基化（即沉默）。在疾病过程中 PITX2 的表观遗传调控可能导致 AR 和 IGF 信号通路的协调控制。总之，我们的研究结果为与前列腺癌从器官受限的雄激素敏感疾病向侵袭性的雄激素不敏感疾病进展相关的表观遗传变化提供了新的见解。
