The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.
The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.
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DOI：
10.1371/journal.pone.0027346
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Tao Q
中科院分区：
文献类型：
--
作者：
Shu XS;Geng H;Li L;Ying J;Ma C;Wang Y;Poon FF;Wang X;Ying Y;Yeo W;Srivastava G;Tsao SW;Yu J;Sung JJ;Huang S;Chan AT;Tao Q
PRDM（含PRDI-BF1和RIZ结构域）蛋白是锌指蛋白，作为表观遗传修饰因子参与多种细胞调控。我们研究了最近发现的PRDM成员PRDM5在多种肿瘤发生中的表观遗传异常和肿瘤抑制功能。半定量RT-PCR显示，PRDM5在人正常组织中广泛表达，但在多种癌细胞系中由于启动子CpG甲基化而经常沉默或下调，包括80%（4/5）的鼻咽癌细胞系、44%（8/18）的食管癌细胞系、76%（13/17）的胃癌细胞系、50%（2/4）的宫颈癌细胞系和25%（3/12）的肝癌细胞系，但在任何永生化正常上皮细胞系中均未表达。在沉默细胞系中，5-aza-2 ' -脱氧胞苷去甲基化处理可以恢复PRDM5的表达。甲基化特异性PCR （MSP）在多原发肿瘤中检测到PRDM5甲基化，包括93%（43/46）鼻咽肿瘤、58%（25/43）食管肿瘤、88%（37/42）胃肿瘤和63%（29/46）肝细胞肿瘤。进一步发现PRDM5是应激反应基因，但当启动子甲基化时，其应激反应受损。异位表达PRDM5显著抑制肿瘤细胞的克隆性，同时抑制TCF/β-catenin依赖性转录，下调CDK4、TWIST1和MDM2癌基因，而下调PRDM5表达可导致细胞增殖增加。ChIP实验显示，PRDM5结合其靶基因启动子并抑制其转录。在细胞系中，PRDM5的表达与活化的β-catenin呈负相关。PRDM5作为肿瘤抑制因子至少部分通过拮抗异常的WNT/β-catenin信号和癌基因表达发挥作用。PRDM5频繁的表观遗传沉默参与多种肿瘤发生，可作为肿瘤生物标志物。
PRDM (PRDI-BF1 and RIZ domain containing) proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5) nasopharyngeal, 44% (8/18) esophageal, 76% (13/17) gastric, 50% (2/4) cervical, and 25% (3/12) hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2′-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP) in multiple primary tumors, including 93% (43/46) nasopharyngeal, 58% (25/43) esophageal, 88% (37/42) gastric and 63% (29/46) hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines. PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.
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DOI：
10.1073/pnas.0700153104
发表时间：
2007-07-24
影响因子：
11.1
作者：
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影响因子：
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