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Promoter hypermethylation-mediated inactivation of LRRC4 in gliomas

Zuping Zhang1, Dan Li, Minghua Wu

  • 1Cancer Research Institute, Central South University, Changsha 410078, Hunan, PR China. zhangzp74@126.com

BMC Molecular Biology
|November 4, 2008
PubMed
Abstract

Insights

Leucine-rich repeat C4 protein (LRRC4) gene inactivation in glioma is frequently caused by promoter methylation, not genetic alteration. Demethylation therapy can restore LRRC4 expression, suggesting its potential as a diagnostic biomarker or therapeutic target.

Area of Science:

  • Neuro-oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Leucine-rich repeat C4 protein (LRRC4) is a brain-specific gene and a potential tumor suppressor.
  • LRRC4 inactivation is common in glioma, but the underlying mechanism remains unclear.
  • Previous studies ruled out genetic alterations as the cause of LRRC4 inactivation in glioma.

Purpose of the Study:

  • To investigate the mechanism controlling LRRC4 expression in glioma.
  • To determine if epigenetic modifications, specifically DNA methylation, regulate LRRC4 expression.
  • To explore the potential of LRRC4 as a biomarker or therapeutic target in glioma.

Main Methods:

  • Cloning and characterization of the LRRC4 promoter using luciferase reporter assays.
  • Analysis of LRRC4 promoter methylation status in glioma cell lines and primary tumors using methylation-specific PCR and bisulfite DNA sequencing.
  • Functional studies involving DNA demethylation using 5-Aza-2'-deoxycytidine to assess LRRC4 mRNA expression and promoter demethylation.

Main Results:

  • The LRRC4 promoter, a GC-rich region lacking TATA/CAAT boxes, was identified.
  • In vitro methylation suppressed LRRC4 promoter activity.
  • LRRC4 promoter methylation was detected in glioma cell lines and primary gliomas but absent in normal brain tissue.
  • DNA demethylation treatment restored LRRC4 mRNA expression and partially demethylated the promoter in glioma cells.

Conclusions:

  • Methylation-mediated inactivation of LRRC4 is a frequent and glioma-specific event.
  • Epigenetic silencing of LRRC4 contributes to glioma development.
  • LRRC4 may serve as a potential biomarker for glioma diagnosis or prognosis and a therapeutic target.

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