Abstract
Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs). Moreover, BCAT1 suppression resulted in downregulation of numerous genes implicated in lipid production and protein synthesis, suggesting its important role in controlling EOC metabolism. Further metabolomic analyses were indicative for significant depletion of most amino acids and different phospho- and sphingolipids following BCAT1 knockdown. Finally, BCAT1 suppression led to significantly prolonged survival time in xenograft model of advanced peritoneal EOC. Taken together, our findings provide new insights about the functional role of BCAT1 in ovarian carcinogenesis and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.
Highlights
Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies [1]
We have recently identified a 425 nt CpG-rich region of the branched chain amino-acid transaminase 1 (BCAT1) gene that is significantly hypomethylated in high grade (HG) serous EOC tumors, compared to normal tissue [8]
This region is positioned within the first intron of BCAT1 gene isoforms I, II and III; it covers a potential control region for BCAT1 isoforms IV and V
Summary
Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies [1]. Applying a more global array-based technology, several studies have demonstrated that DNA methylation changes in ovarian cancer are cumulative with disease progression and chemotherapy (CT) resistance [5,6,7]. Using a similar approach (methylated DNA immunoprecipitation coupled to CpG island tiling arrays) we have recently shown that DNA hypermethylation occurs in all (including less invasive/early) stages of ovarian tumorigenesis. BCAT enzymes comprise two isoforms: BCAT1 (cytosolic) and BCAT2 (mitochondrial) Both isoforms regulate the first step in degradation of branched-chain amino acids (BCAAs) including leucine, isoleucine and valine, which are essential for cellular metabolism and growth [9]. Recent studies were indicative for the important role of BCAT1 in the progression of several malignancies, including medulloblastomas, nonseminomas, colorectal and nasopharyngeal carcinomas and glioblastomas [12,13,14,15,16]. The role of BCAAs metabolism in cancer pathogenesis has been a topic of interest [17]
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