Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway

Takehiro Yamamoto, Naoharu Takano, Kyoko Ishiwata, Mitsuyo Ohmura, Yoshiko Nagahata, Tomomi Matsuura, Aki Kamata, Kyoko Sakamoto, Tsuyoshi Nakanishi, Akiko Kubo, Takako Hishiki and Makoto Suematsu ()
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Takehiro Yamamoto: Keio University School of Medicine
Naoharu Takano: Keio University School of Medicine
Kyoko Ishiwata: Keio University School of Medicine
Mitsuyo Ohmura: Keio University School of Medicine
Yoshiko Nagahata: Keio University School of Medicine
Tomomi Matsuura: Keio University School of Medicine
Aki Kamata: Keio University School of Medicine
Kyoko Sakamoto: Keio University School of Medicine
Tsuyoshi Nakanishi: Keio University School of Medicine
Akiko Kubo: Keio University School of Medicine
Takako Hishiki: Keio University School of Medicine
Makoto Suematsu: Keio University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: Abstract Haem oxygenase (HO)-1/carbon monoxide (CO) protects cancer cells from oxidative stress, but the gas-responsive signalling mechanisms remain unknown. Here we show using metabolomics that CO-sensitive methylation of PFKFB3, an enzyme producing fructose 2,6-bisphosphate (F-2,6-BP), serves as a switch to activate phosphofructokinase-1, a rate-limiting glycolytic enzyme. In human leukaemia U937 cells, PFKFB3 is asymmetrically di-methylated at R131 and R134 through modification by protein arginine methyltransferase 1. HO-1 induction or CO results in reduced methylation of PFKFB3 in varied cancer cells to suppress F-2,6-BP, shifting glucose utilization from glycolysis toward the pentose phosphate pathway. Loss of PFKFB3 methylation depends on the inhibitory effects of CO on haem-containing cystathionine β-synthase (CBS). CBS modulates remethylation metabolism, and increases NADPH to supply reduced glutathione, protecting cells from oxidative stress and anti-cancer reagents. Once the methylation of PFKFB3 is reduced, the protein undergoes polyubiquitination and is degraded in the proteasome. These results suggest that the CO/CBS-dependent regulation of PFKFB3 methylation determines directional glucose utilization to ensure resistance against oxidative stress for cancer cell survival.

Date: 2014
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DOI: 10.1038/ncomms4480

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