High incidence of LRAT promoter hypermethylation in colorectal cancer correlates with tumor stage

Yu Wei Cheng, Hanna Pincas, Jianmin Huang, Emmanuel Zachariah, Zhaoshi Zeng, Daniel A. Notterman, Philip Paty, Francis Barany

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Lecithin:retinol acyltransferase (LRAT) is a major enzyme involved in vitamin A/retinol metabolism, which regulates various physiological processes like cell proliferation and differentiation. LRAT expression is reduced in numerous cancers, yet the underlying mechanisms have remained undefined. We hypothesized that methylation silencing may contribute to decreased LRAT gene expression in colorectal cancer (CRC). LRAT hypermethylation status was analyzed in five CRC cell lines, 167 colorectal tumors, and 69 adjacent normal colonic mucosae, using a quantitative bisulfite/PCR/LDR/Universal Array assay. LRAT transcription levels were determined by real-time RT-PCR in a subset of tumors and matched normal tissues and in CRC cell lines that were treated with a demethylating agent, 5-aza-2′-deoxycytidine. The incidence of LRAT hypermethylation was significantly higher in colorectal tumors than in adjacent normal mucosae (p = 0.0025). Aberrant methylation occurred in 51 % of microsatellite-stable CRCs, in 84 % of microsatellite-unstable CRCs, and in 12 out of 13 colonic polyps. The number of hypermethylated LRAT events was inversely correlated with CRC stage (p < 0.0001). Importantly, LRAT hypermethylation was associated with decreased mRNA level in CRC clinical specimens, and demethylation treatment resulted in LRAT transcriptional reactivation. Our data support the idea that LRAT promoter hypermethylation associates with LRAT gene expression in CRC. The higher frequency of LRAT hypermethylation in colonic polyps and early-stage CRCs indicates that it may occur early in malignant progression.

Original languageEnglish (US)
Article number254
Pages (from-to)1-8
Number of pages8
JournalMedical Oncology
Volume31
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Keywords

  • Colorectal cancer
  • CpG methylation
  • LRAT
  • Microsatellite instability
  • Thermostable ligase
  • Universal microarray

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