"Lysine Demethylase 5a (Kdm5a) regulates metabolic activity and tumorig" by Nicole Schreiner, Lisa Fahr et al.
 

Lysine Demethylase 5a (Kdm5a) regulates metabolic activity and tumorigenic potential of murine pancreatic cancer cells

Document Type

Conference Proceeding

Publication Date

12-5-2024

Publication Title

Pancreatology

Abstract

Background: Lysine Demethylase 5a (KDM5A) is a histone demethylase known for selective removal of tri-methylation from lysine 4 of histone 3 (H3K4me3), a modification linked to active transcription. Crucial cellular processes implicated in cancer progression, such as senescence, cell cycle regulation and motility are known to be tightly regulated by KDM5A. Own previous studies revealed deregulation of H3K4me3 modifications with concomitant increased expression of Kdm5a in murine pancreatic tumor cells, indicating an oncogenic role. We hypothesize that Kdm5a-mediated removal of H3K4me3 from specific target genes contributes to a more aggressive tumor phenotype. Methods: A knockout of Kdm5a (K5KO) was generated in murine pancreatic tumor cells utilizing the CRISPR/Cas9 system. Phenotypic characterization of K5KO cells included assays for colony formation, proliferation, migration, cell cycle, cancer stem cell potential, and respiratory activity. Transcriptional changes were assessed via RNA-seq, while ChIP-seq was performed to evaluate the abundance of H3K4me3 and H3K4me1. Metabolomic analyses was conducted to verify alterations of metabolites in pathways of interest. The tumor formation capacity of K5KO was investigated using orthotopic and metastatic mouse models. Results: Deletion of Kdm5a in murine pancreatic cancer cells resulted in a pronounced increase of H3K4me3 levels, accompanied by transcriptional changes leading to an upregulation of genes involved in carbohydrate metabolic processes. On the other hand, genes regulating oxidative stress are downregulated in K5KO tumor cells. K5KO clones exhibited significant reduction in proliferation, migration, colony formation and the expression of cancer stem cell markers. Furthermore, they displayed changes in the oxygen consumption and extracellular acidification rate, accompanied by a significant upregulation of the metabolites within the TCA cycle and downregulation in the Glycolysis pathway. Experiments conducted in vivo displayed a complete loss of tumor-forming capacity of K5KO cells. Conclusions: Our findings corroborate a pro-tumorigenic role of Kdm5a for pancreatic cancer. We demonstrated that Kdm5a alters H3K4me3 modifications and regulates the metabolic activity and aggressiveness of pancreatic cancer cells in vitro and in vivo. K5KO leads to H3K4me3 accumulation and an epigenetic reprogramming, shifting the tumor cellś metabolic reliance from glycolysis to oxidative phosphorylation.

Volume

24

First Page

e94

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