Histone methyltransferase GLP epigenetically activates GPCPD1 to sustain cancer cell metastasis and invasion

Abstract

AbstractDisordered choline metabolism is associated with tumor progression. Glycerophosphocholine phosphodiesterase 1 (GPCPD1) is critical for cleaving glycerophosphocholine (GPC) to produce choline. However, whether and how GPCPD1 is epigenetically regulated remains largely unknown. In the current study, we report that histone H3 lysine 9 (H3K9) methyltransferase GLP (G9a-like Protein) is essential for transcriptional activation of GPCPD1 through H3K9me1 to promote tumor cell migration and invasion. Knocking down GLP or inhibiting its methyltransferase activity impaired GPCPD1 expression and decreased the choline levels. Importantly, we confirmed that both GPCPD1 and choline levels are positively correlated with cancer cell migration. The reduced migration and invasion of GPCPD1-knockdown cells were rescued by choline treatment. Interestingly, GPCPD1 gene expression was found regulated by transcription factor Krüppel-like Factor 5 (KLF5). KLF5 recruitment was GLP-dependent and was indispensable for GPC-induced GPCPD1 expression. These data suggest that GLP promotes tumor cell migration and invasion by transcriptionally activating GPCPD1. GLP and KLF5 are potential therapeutic targets in future cancer treatment.