PCNA has specific functions in regulation of metabolism in haematological cells

Abstract

PCNAs essential roles in DNA replication and repair are well established, while its recently discovered cytosolic roles are less explored. Here we show that impairing PCNAs cytosolic scaffold functions led to massive changes in cellular signaling, and most strikingly, a strong reduction in glycolytic metabolite and nucleoside phosphate pools in haematological cancer cells. This was not detected in cells from solid tissues nor in primary monocytes from healthy donors. However, lipopolysaccharide stimulated monocytes responded to targeting PCNAs scaffold function similarly to haematological cancer cells, suggesting that cellular stress is an important factor for the observed response. Integrated transcriptome, proteome and metabolome analysis revealed that pathways involved in protein stability/folding and immune responses were affected in haematopoietic cancer cells. Altogether, our data suggests that PCNA has an important role in regulation of cytoplasmic stress via regulation of central carbon metabolism in haematological cells, which potentially can be targeted in cancer treatment. HighlightA strong reduction in glycolytic metabolites and the nucleoside phosphate pools was detected in haematological cancer cells upon inhibiting PCNA scaffold functions. These metabolic changes were not found in cancer cells from other tissues, indicating a special role of PCNA in regulation of metabolism in cells of haematological origin.