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Epigenetic silencing of cellular retinol-binding proteins in nasopharyngeal carcinoma

Joseph Kwong1, Kwok-Wai Lo, Lillian Shuk-Nga Chow

  • 1Department of Anatomical and Cellular Pathology, Hong Kong, SAR, China.

Neoplasia (New York, N.Y.)
|February 22, 2005
PubMed

Insights

Epigenetic silencing of cellular retinol-binding proteins (CRBPI and CRBPIV) and retinoic acid receptor (RARbeta2) occurs in nasopharyngeal carcinoma (NPC). This disruption of retinoid signaling is linked to NPC development and responsiveness to retinoic acid therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Aberrant retinoid signaling is implicated in human cancers.
  • Retinoic acid receptor (RAR) beta2 inactivation was previously observed in nasopharyngeal carcinoma (NPC).
  • Cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs) are key in retinoid metabolism and signaling.

Purpose of the Study:

  • To investigate the expression and epigenetic regulation of CRBPs, CRABPs, RARs, and retinoid X receptors (RXRs) in NPC.
  • To determine the role of CRBPI and CRBPIV in NPC tumorigenesis.
  • To explore the potential of targeting these epigenetic alterations for cancer therapy.

Main Methods:

  • Analysis of CRBP, CRABP, RAR, and RXR expression in NPC cell lines and xenografts.
  • Investigation of CpG island methylation in CRBPI and CRBPIV promoter regions.
  • Treatment of NPC cell lines with 5-aza-2'-deoxycytidine (a DNA methyltransferase inhibitor) to assess gene reexpression.
  • Analysis of CRBPI, CRBPIV, and RARbeta2 methylation in primary NPC tumors.

Main Results:

  • Transcriptional silencing of CRBPI and CRBPIV was observed in NPC cell lines and xenografts, in addition to RARbeta2.
  • Hypermethylation of CRBPI and CRBPIV CpG islands correlated with their reduced expression.
  • CRBPIV promoter hypermethylation was identified as a novel mechanism of inactivation in human cancer.
  • Simultaneous hypermethylation of CRBPI, CRBPIV, and RARbeta2 was frequently detected in primary NPC tumors (87.8% for CRBPI, 54.2% for CRBPIV).
  • Treatment with 5-aza-2'-deoxycytidine restored CRBP1 and CRBPIV gene expression in NPC cell lines.

Conclusions:

  • Epigenetic inactivation of CRBPI and CRBPIV through promoter hypermethylation is a significant event in NPC tumorigenesis.
  • These epigenetic alterations contribute to the loss of retinoic acid responsiveness in NPC.
  • CRBPIV inactivation by hypermethylation is reported for the first time in human cancer.
  • Simultaneous epigenetic disruption of CRBPs and RARbeta2 highlights a broader role for aberrant retinoid signaling in NPC development.

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