Masalmeh, R. H. A. | Search bioRxiv

bioRxiv2024

FAK modulates glioblastoma stem cell energetics via actomyosin contractility: regulation of glycolysis and mitochondrial function

Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). We show that focal adhesion kinase (FAK), a mediator of integrin-ECM signalling, is driving cellular energetics in a stem cell model of glioblastoma (GBM). FAK gene deletion inhibits both glycolysis and glutamine oxidation, with increased mitochondrial fragmentation and elevated phosphorylation of the mitochondrial protein MTFR1L at S235. Simultaneously, FAK loss causes a mesenchymal to epithelial transition, enhanced acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19) and impaired cell migration/invasiveness. Rho-kinase (ROCK) inhibitors suppress p-MLC (S19) and restore glutamine oxidation and elongation of mitochondria. Thus, FAK is a key regulator of both glycolysis and glutamine oxidation mediated by acto-myosin contractility that controls both cell and mitochondrial morphology. Moreover, FAK-dependent cellular energetics are coincident properties with GBM stem cell migration, invasiveness and tumour growth in vivo.

cancer biology↗

bioRxiv2019

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

The aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CGIs are targeted by de novo DNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels of de novo DNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that instead de novo DNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

genetics↗