FTO promotes colorectal cancer progression and chemotherapy resistance via demethylating G6PD/PARP1

SEE PDF] G6PD, as first key enzyme of pentose phosphate pathway (PPP), is main producer of NADPH.4 PARP1 plays an indispensable role in DNA damage repair, especially DNA double-strand breaks (DSB). [...]to explore whether FTO regulates redox homeostasis and DNA repair process are mediated by G6PD/PARP1 through m6A modification; First, we performed real-time PCR and western blotting assay and found that FTO regulates the mRNA and protein levels of G6PD and PARP1 (Figure 3A,B; Figure S4A–C). [...]we identified YTHDF2 as G6PD/PARP1 m6A reader protein (Figure 3D), which mediates the degradation of mRNA.5 Indeed, we found that the G6PD/PARP1 mRNA stability was markedly decreased upon FTO knockdown (Figure 3E), while, the decreased G6PD/PARP1 mRNA stability was restored by knockdown of YTHDF2 in FTO depletion cells (Figure 3F; Figure S4G). [...]the cell proliferation, DNA damage, and cell senescence were restored not only by overexpression of G6PD, but also by overexpression of PARP1 (Figure 3L-Q; Figure S4J–L).