Epigenetic control of group V phospholipase A2 expression in human malignant cells

• Published in: Tumor biology Vol. 37; no. 6; pp. 8097 - 8105
• Main Authors: Menschikowski, Mario, Hagelgans, Albert, Nacke, Brit, Jandeck, Carsten, Mareninova, Olga A., Asatryan, Liana, Siegert, Gabriele
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.06.2016
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Cell Proliferation; Cells, Cultured; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Group V Phospholipases A2 - genetics; Humans; Neoplasms - genetics; Neoplasms - pathology; Original Article; Promoter Regions, Genetic - genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sulfites - chemistry; DNA methylation; Group V sPLA; Solid cancer cells; Leukaemia; Group V sPLA2
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-015-4670-x

Secreted phospholipases A 2 (sPLA 2 ) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA 2 s expression in cancer cells, but group V sPLA 2 (GV-PLA 2 ) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA 2 expression in different cell lines originating from leukaemia and solid cancers. In blood leukocytes from leukaemic patients, levels of GV-PLA 2 transcripts were significantly lower in comparison to those from healthy individuals. Similarly, in DU-145 and PC-3 prostate and CAL-51 and MCF-7 mammary cancer cell lines, levels of GV-PLA 2 transcripts were significantly lower in relation to those found in normal epithelial cells of prostate or mammary. By sequencing and methylation-specific high-resolution melting (MS-HRM) analyses of bisulphite-modified DNA, distinct CpG sites in the GV-PLA 2 promoter region were identified that were differentially methylated in cancer cells in comparison to normal epithelial and endothelial cells. Spearman rank order analysis revealed a significant negative correlation between the methylation degree and the cellular expression of GV-PLA 2 ( r  = −0.697; p  = 0.01). The effects of demethylating agent (5-aza-2′-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on GV-PLA 2 transcription in the analysed cells confirmed the importance of DNA methylation and histone modification in the regulation of the GV-PLA 2 gene expression in leukaemic, prostate and mammary cancer cell lines. The exposure of tumour cells to human recombinant GV-PLA 2 resulted in a reduced colony forming activity of MCF-7, HepG2 and PC-3 cells, but not of DU-145 cells suggesting a cell-type-dependent effect of GV-PLA 2 on cell growth. In conclusion, our results suggest that epigenetic mechanisms such as DNA methylation and histone modification play an important role in downregulation of GV-PLA 2 expression in cancer cells.