Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer
✍ Scribed by Paula S. Lee; Vanessa S. Teaberry; Amy E. Bland; Zhiqing Huang; Regina S. Whitaker; Tsukasa Baba; Shingo Fujii; Angeles Alvarez Secord; Andrew Berchuck; Susan K. Murphy
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- French
- Weight
- 460 KB
- Volume
- 126
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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.