Expression of lysine demethylase 5a (Kdm5a) influences tumour aggressiveness in murine pancreatic cancer cells

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Conference Proceeding

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Abstract Background: Lysine demethylase 5a (KDM5A) is a histone demethylase that specifically eliminates transcriptionally activating tri-methylation of lysine 4 of histone 3 (H3K4me3). KDM5A coordinates many crucial cell events, such as cellular senescence, cell cycle, cell motility and epithelial-to-mesenchymal transition (EMT), which are often deregulated in cancer. In own previous studies, we detected a loss of H3K4me3 modifications at pancreas differentiation genes with a concomitant increased expression of Kdm5a in murine pancreatic tumour lesions, indicating an oncogenic role for Kdm5a. Hence, we suppose that Kdm5a-driven removal of H3K4me3 at pancreas differentiation genes during tumour progression results in an undifferentiated, more aggressive phenotype. Methods: The role of KDM5A in human pancreatic cancer was determined using in silico analysis. A knockout of Kdm5a (Kdm5a-KO) was generated in murine pancreatic tumour cells using the CRISPR/Cas9 system. The Kdm5a-KO was confirmed by sanger sequencing and immunoblot analysis. The Kdm5a-KO tumour cells were characterised phenotypically by cell assays determining colony formation, proliferation, migration, cell cycle and cancer stem cell potential. Transcriptional changes in Kdm5a-KO tumour cells were analysed by RNA sequencing. Results: High expression of KDM5A in pancreatic cancer patient tissue was associated with shorter progression free intervals and worse overall survival. The top 100 positively correlated genes of KDM5A were linked with ‘signalling pathways regulating pluripotency of stem cells’, whereas negatively correlated genes were related to mitochondrial and respiratory regulations. Upon Kdm5a-KO, overall H3K4me3 levels were increased and Kdm5a-KO tumour cells showed significant reduction in proliferation, migration, colony formation and the expression of cancer stem cell markers CD24 and CD44 in comparison to control cells. Furthermore, Kdm5a-KO cells demonstrated a delayed escape from the G0 cell cycle phase after medium starvation. Conclusion: Our data suppose that KDM5A induces cancer stem cell signalling pathways, while a loss of Kdm5a caused reduced abundance of cancer stem cell markers and a less aggressive phenotype of the murine pancreatic tumour cells. An overall enrichment of the activating histone modification H3K4me3 upon Kdm5a deletion suggests an epigenetic reprogramming towards a more differentiated phenotype.

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