Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribos...Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribose. How cancer cells modulate PPP activity in response to glucose supply remains unclear. Here we show that ribose-5-phosphate isomerase A(RPIA), an enzyme in PPP, directly interacts with co-activator associated arginine methyltransferase 1(CARM1) and is methylated at arginine 42(R42). R42 methylation up-regulates the catalytic activity of RPIA. Furthermore, glucose deprivation strengthens the binding of CARM1 with RPIA to induce R42 hypermethylation. Insufficient glucose supply links to RPIA hypermethylation at R42, which increases oxidative PPP flux. RPIA methylation supports ROS clearance by enhancing NADPH production and fuels nucleic acid synthesis by increasing ribose supply. Importantly, RPIA methylation at R42 significantly potentiates colorectal cancer cell survival under glucose starvation. Collectively, RPIA methylation connects glucose availability to nucleotide synthesis and redox homeostasis.展开更多
基金supported by the Ministry of Science and Technology(2019YFA0801703)the National Natural Science Foundation of China(81790250,81790253 and 91959202)the Innovation Program of Shanghai Municipal Education Commission(N173606)。
文摘Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway(PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribose. How cancer cells modulate PPP activity in response to glucose supply remains unclear. Here we show that ribose-5-phosphate isomerase A(RPIA), an enzyme in PPP, directly interacts with co-activator associated arginine methyltransferase 1(CARM1) and is methylated at arginine 42(R42). R42 methylation up-regulates the catalytic activity of RPIA. Furthermore, glucose deprivation strengthens the binding of CARM1 with RPIA to induce R42 hypermethylation. Insufficient glucose supply links to RPIA hypermethylation at R42, which increases oxidative PPP flux. RPIA methylation supports ROS clearance by enhancing NADPH production and fuels nucleic acid synthesis by increasing ribose supply. Importantly, RPIA methylation at R42 significantly potentiates colorectal cancer cell survival under glucose starvation. Collectively, RPIA methylation connects glucose availability to nucleotide synthesis and redox homeostasis.
