title: The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xing-sheng
authors.initials: XS
authors.lastname: Shu
authors.forename: Hua
authors.initials: H
authors.lastname: Geng
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.forename: Chunhong
authors.initials: C
authors.lastname: Ma
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wang
authors.forename: Fan Fong
authors.initials: FF
authors.lastname: Poon
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Ying
authors.forename: Winnie
authors.initials: W
authors.lastname: Yeo
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Shi
authors.initials: S
authors.lastname: Huang
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D004268:DNA-Binding Proteins / Q000502:physiology*; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; C487762:PRDM5 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin
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