A Systems Biology Study Of The Cellular Metabolic Regulation Of Jhdm1b In Tumor Cells

Metabolic reprogramming, such as Warburg effect and glutaminolysis, is a hallmark of primary and metastatic human tumors. To satisfy the requirements of energy production and biomass synthesis for rapid proliferation, tumor cells tend to choose a faster but less efficient way to utilize nutrients, such as glucose and glutamine. Epigenetic alterations also play key roles in tumor development and growth. Recent study indicates that cell metabolism can be shaped by the epigenetic landscape of chromatin by regulating DNA and histone modification.In mammalian cells, the histone lysine methylation state is related with histone lysine methyltransferases (KMTs) and demethylases (KDMs). Recent findings suggest that KMTs and KDMs may be important in cell metabolism.Jhdmlb/Kdm2b/Fbx110, a member of Jhdm (JmjC-domain-containing histone demethylase) family, is an H3K4/K36histone demethylase. Jhdmlb is overexpressed in various types of cancer, and it is critical to both cellular senescence and tumorigenesis. Recently, some evidence has shown that Jhdmlb plays an important role in regulating cell metabolism. Microarray experiments revealed that about50%of the Jhdmlb target genes, such as RIP3, are linked to cell metabolism. Moreover, RIP3regulates several metabolic enzymes, such as glycogen phosphorylase (PYGL), glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase1(GLUD1) that enhance the metabolism-associated ROS production.Although previous work indicates that Jhdmlb may be relevant to metabolic alterations in cancer cells, a systematic investigation on the metabolic regulation of Jhdmlb in tumor cells remains lacking. In this work, we established the13C stable isotope-resolved metabolomics analysis platform in mammal cells and used U-13C glucose/glutamine and1,2-13C glucose as carbon sources to study the differences in carbon central metabolism between Jhdmlb knockdown and wild-type HeLa cells based on two complementary approaches:gas chromatography-mass spectroscopy (GC-MS) and nuclear magnetic resonance (NMR). Our results reveal that Jhdmlb is an RIP3-dependent regulator of cancer metabolism and may aid in the function exploration of histone demethylases in tumor cellular metabolic regulation which can potentially provide new ideas for cancer therapy.