Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer

Int J Cancer. 2010 Mar 15;126(6):1378-89. doi: 10.1002/ijc.24797.

Abstract

We previously found that the gene encoding the Myelin and Lymphocyte protein, MAL, was among the most highly expressed genes in serous ovarian cancers from short-term survivors (<3 years) relative to those of long-term survivors (>7 years). In the present study, we have found that this difference in expression is partially attributable to differences in DNA methylation at a specific region within the MAL promoter CpG island. While MAL was largely unmethylated at the transcription start site (Region 1; -48 to +73 bp) in primary serous ovarian cancers, methylation of an upstream region (Region 2; -452 to -266 bp) was inversely correlated with MAL transcription in the primary cancers (R = -0.463) and ovarian cancer cell lines (R = -0.444). Following treatment of the OVCA432 cell line with 5-azacytidine, methylation of Region 2 decreased from 73.3% to 34.7% (p = 0.007) while Region 1 was unaffected. This was accompanied by a 10-fold increase in MAL expression. Since MAL transcripts are elevated in tumors from short-term survivors, all of whom were treated with platinum-based therapy, MAL may have a role in cisplatin response. We therefore determined the 50% growth inhibitory dose of cisplatin in 30 ovarian cancer cell lines and compared this to MAL expression. MAL transcript levels were higher in the resistant ovarian cell lines (p = 0.04). MAL methylation status may therefore serve as a marker of platinum sensitivity while MAL protein may be a target for development of novel therapies aimed at enhancing sensitivity to platinum-based drugs in ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Azacitidine / pharmacology
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • DNA Methylation*
  • Drug Resistance, Neoplasm / genetics
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Transport Proteins / genetics*
  • Molecular Sequence Data
  • Myelin Proteins / genetics*
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Oligonucleotide Array Sequence Analysis
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Promoter Regions, Genetic / genetics*
  • Proteolipids / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA / methods
  • Survivors

Substances

  • Antineoplastic Agents
  • MAL protein, human
  • Membrane Transport Proteins
  • Myelin Proteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Proteolipids
  • Azacitidine
  • Cisplatin