Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer.
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.
Lee
Paula S
PS
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27708, USA.
Teaberry
Vanessa S
VS
Bland
Amy E
AE
Huang
Zhiqing
Z
Whitaker
Regina S
RS
Baba
Tsukasa
T
Fujii
Shingo
S
Secord
Angeles Alvarez
AA
Berchuck
Andrew
A
Murphy
Susan K
SK
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
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