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Epigenetic silencing of the PTEN gene in melanoma

Alireza Mirmohammadsadegh1, Alessandra Marini, Sandeep Nambiar

  • 1Department of Dermatology, Heinrich-Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany.

Cancer Research
|July 5, 2006
PubMed

Insights

Epigenetic silencing of the PTEN tumor suppressor gene via promoter methylation is common in metastatic melanoma. This methylation in circulating DNA correlates with tumor tissue and reduces PTEN expression, potentially driving melanoma progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The PTEN gene is a critical tumor suppressor frequently inactivated in various cancers, including melanoma.
  • While PTEN deletions/mutations are infrequent in melanoma, low PTEN protein levels suggest alternative inactivation mechanisms.
  • Epigenetic silencing, particularly promoter methylation, is a potential pathway for PTEN inactivation in melanoma.

Purpose of the Study:

  • To investigate epigenetic silencing of the PTEN gene in melanoma.
  • To determine the prevalence and significance of PTEN promoter methylation in circulating DNA of melanoma patients.
  • To explore the correlation between PTEN methylation, PTEN expression, and AKT pathway activity.

Main Methods:

  • Quantitative positional methylation analysis (pyrosequencing) of the PTEN promoter in DNA from melanoma patient sera and tumor tissues.
  • Taqman reverse transcription-PCR to assess PTEN mRNA levels.
  • In vitro kinase assays using BLM melanoma cells treated with a demethylation agent (5-aza-2'-deoxycytidine).

Main Results:

  • Significant PTEN promoter methylation was detected in 62% of circulating DNA from metastatic melanoma patients' sera.
  • PTEN methylation levels in serum DNA correlated with methylation in corresponding tumor tissues.
  • Increased PTEN methylation was associated with decreased PTEN transcription and, upon demethylation, led to reduced AKT activity in melanoma cells.

Conclusions:

  • Epigenetic silencing through PTEN promoter methylation is a relevant mechanism for inactivating this tumor suppressor in melanoma.
  • This silencing contributes to melanoma development by derepressing the AKT pathway.
  • PTEN methylation in circulating DNA serves as a potential biomarker for melanoma.

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