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

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; 248 to 173 bp) in primary serous ovarian cancers, methylation of an upstream region (Region 2; 2452 to 2266 bp) was inversely correlated with MAL transcription in the primary cancers (R 5 20.463) and ovarian cancer cell lines (R 5 20.444). Following treatment of the OVCA432 cell line with 5-azacytidine, methylation of Region 2 decreased from 73.3% to 34.7% (p 5 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 5 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.

DNA methylation profiles in ovarian cancer: Implication in diagnosis and therapy (Review)

“…In addition to the loss of expression due to DNA methylation, it was shown that hypomethylation along with an increase in expression of the myelin and lymphocyte protein ( MAL ) gene is associated with platinum resistance (62). Hypomethylation and upregulation of the ABCG2 multidrug transporter gene was also shown to occur during chemoresistance in two ovarian carcinoma cell lines (81).…”

Gene Expression: Protein Interaction Systems Network Modeling Identifies Transformation-Associated Molecules and Pathways in Ovarian Cancer

“…Bivalent and trivalent combinations of histone modifications are also reported in cancer (29). In an ongoing study, we have profiled the epigenetic status of genes in the A4 cell model on a genome-wide scale through Me-DIP for DNA methylation and ChIP-on-chip for histone methylation (K4, K9, and K27) from which we extracted data relating to SeOvCa genes MAL, MEST, PTGIS, PAPSS2, EFEMP1, and FBN1 because these are reported to be epigenetically regulated in human malignancies (18,(30)(31)(32)(33)(34)(35)(36). The transformed state was strikingly associated with hypomethylated promoters of the upregulated genes (MAL and MEST); this was further supported by two activation K4 marks upstream of the MAL transcription start site (TSS) and an enriched K4-K9 bivalent mark upstream of the MEST-TSS (Fig.…”

DNA methylation of HOXD3 as a marker of prostate cancer progression

“…10 Gene-specific anomalies are also common, however, and can lead to the inactivation of tumor suppressor genes or to the activation of oncogenes. 8,11 The former arises through hypermethylation of promoters, whereas the latter occurs when promoter CpG islands become hypomethylated. Importantly, promoter methylation events are being recognized for their potential as both diagnostic and prognostic indicators for a variety of malignancies including bladder, prostate, and colon cancers.…”