BCL6 function and platin resistance in epithelial ovarian cancer

Purpose:

Identification of methylated genes with functional involvement in cisplatin-resistance development of epithelial ovarian cancer (EOC).

Methods:

Genome-wide analyses identified hypermethylated CpG-islands in (i) three isogenic resistant cell lines in comparison to the parental cells and (ii) primary type-II-EOC tumors of resistant patients (n = 5) and sensitive patients with or without relapse during 3 years of follow up (n = 11 and n = 7, respectively). Gene expression analyses were done by qRT-PCR for BCL6 and functional analyses in-vitro were conducted after pharmacological inhibition of BCL6 gene function.

Results:

Experiments revealed 37 hypermethylated genes in resistant cell lines and 76 genes with hypermethylation in at least 3/5 resistant EOC but without hypermethylation in sensitive tumors without relapse. Only BCOR (BCL6 co-repressor) was identified in both sets. BCL6 itself was additionally identified as hypermethylated in resistant primary tumors. The comparison of BCL6 gene expression between parental and resistant cells after cisplatin treatment revealed a time- and concentration dependent up-regulation most pronounced in sensitive cells. Importantly, pharmacologic inhibition of the BCL6 function by treatment with the novel inhibitor FX1 increased the IC50 value of cisplatin by 1.5- to 3.8-fold in different EOC cell lines. The effect size was inversely correlated with the cell line specific resistance to cisplatin.

Conclusions:

Loss of BCL6 function may represent a requirement for the resistant phenotype of EOC.