Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, Discipline of Medicine, The University of Adelaide and Hanson Institute, Adelaide, Australia.
Prostate. 2013 Jan;73(2):182-93. doi: 10.1002/pros.22554. Epub 2012 Jul 10.
Krüppel-like factor (KLF) 6 is a candidate tumor suppressor gene in prostate cancer, but the mechanisms contributing to its loss of expression are poorly understood. We characterized KLF6 expression and DNA methylation status during prostate tumorigenesis in humans and mice.
KLF6 expression was assessed in matched human non-malignant (NM) and tumor prostate tissues (n = 22) by quantitative real-time PCR (qPCR) and in three independent human prostate cancer cohorts bioinformatically. QPCR for KLF6 expression and methylation-sensitive PCR (MSP) were performed in human prostate LNCaP cancer cells after 5-aza-2'-deoxycytidine treatment. Klf6 protein levels and DNA promoter methylation were assessed in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors by immunohistochemistry and MSP, respectively.
KLF6 splice variants expression was increased (P = 0.0015) in human prostate tumors compared to NM tissues. Overall, KLF6 was decreased in metastatic compared to primary prostate cancers and reduced expression in primary tumors was associated with a shorter time to relapse (P = 0.0028). Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in up-regulation of KLF6 expression (two-fold; P = 0.002) and a decrease in DNA methylation of the KLF6 promoter in LNCaP cells. Klf6 protein levels significantly decreased with progression in the TRAMP model of prostate cancer (P < 0.05), but there was no difference in Klf6 promoter methylation.
KLF6 expression was decreased in both clinical prostate cancer and the TRAMP model with disease progression, but this could not be explained by DNA methylation of the KLF6 promoter.
Krüppel 样因子（KLF）6 是前列腺癌的候选肿瘤抑制基因，但导致其表达缺失的机制尚不清楚。我们在人类和小鼠中研究了前列腺肿瘤发生过程中 KLF6 的表达和 DNA 甲基化状态。
通过定量实时 PCR（qPCR）评估 22 对匹配的人类非恶性（NM）和肿瘤前列腺组织中的 KLF6 表达，并通过三个独立的人类前列腺癌队列进行生物信息学分析。用 5-氮杂-2'-脱氧胞苷处理人前列腺 LNCaP 癌细胞后，进行 KLF6 表达的 qPCR 和甲基化敏感 PCR（MSP）。通过免疫组织化学和 MSP 分别评估 TRansgenic Adenocarcinoma of Mouse Prostate（TRAMP）肿瘤中的 Klf6 蛋白水平和 DNA 启动子甲基化。
与 NM 组织相比，人类前列腺肿瘤中的 KLF6 剪接变体表达增加（P = 0.0015）。总体而言，与原发性前列腺癌相比，转移性前列腺癌中 KLF6 表达降低，原发性肿瘤中表达降低与复发时间缩短相关（P = 0.0028）。用去甲基化剂 5-氮杂-2'-脱氧胞苷处理后，LNCaP 细胞中 KLF6 表达上调（两倍；P = 0.002），KLF6 启动子的 DNA 甲基化减少。在前列腺癌的 TRAMP 模型中，Klf6 蛋白水平随疾病进展显著降低（P < 0.05），但 Klf6 启动子甲基化没有差异。
在临床前列腺癌和 TRAMP 模型中，KLF6 表达随着疾病的进展而降低，但这不能用 KLF6 启动子的 DNA 甲基化来解释。
