title: 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; -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.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Lee
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Teaberry
authors.forename: Amy E
authors.initials: AE
authors.lastname: Bland
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.forename: Regina S
authors.initials: RS
authors.lastname: Whitaker
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.forename: Shingo
authors.initials: S
authors.lastname: Fujii
authors.forename: Angeles Alvarez
authors.initials: AA
authors.lastname: Secord
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000235:genetics*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011510:Proteolipids / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA / Q000379:methods; D017741:Survivors
chemical_list: D000970:Antineoplastic Agents; C569026:MAL protein, human; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; D001374:Azacitidine; D002945:Cisplatin