Glyceraldehyde‐3‐phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase

Up‐regulated glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine‐induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain‐deleted GAPDH (GAPDHΔCD) affected metabolism, up‐regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down‐regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDHΔCD similarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining. Conclusion: GAPDH increases histone methylation levels by up‐regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (Hepatology 2017;66:631–645).

[1]  S. Romeo,et al.  Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. , 2014, World journal of gastroenterology.

[2]  Yves Gibon,et al.  GMD@CSB.DB: the Golm Metabolome Database , 2005, Bioinform..

[3]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[4]  M. Karin,et al.  Immunity, Inflammation, and Cancer , 2010, Cell.

[5]  Henning Redestig,et al.  TargetSearch - a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data , 2009, BMC Bioinformatics.

[6]  R. Deberardinis,et al.  NRF2 regulates serine biosynthesis in non-small cell lung cancer , 2015, Nature Genetics.

[7]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[8]  R. Roeder,et al.  S Phase Activation of the Histone H2B Promoter by OCA-S, a Coactivator Complex that Contains GAPDH as a Key Component , 2003, Cell.

[9]  G. A. Grant.  D-3-Phosphoglycerate Dehydrogenase , 2018, Front. Mol. Biosci..

[10]  M. Sirover,et al.  Subcellular dynamics of multifunctional protein regulation: Mechanisms of GAPDH intracellular translocation , 2012, Journal of cellular biochemistry.

[11]  Lihua Jiao,et al.  Apelin inhibits the development of diabetic nephropathy by regulating histone acetylation in Akita mouse , 2014, The Journal of physiology.

[12]  M. Bonafè,et al.  Aberrant Metabolism in Hepatocellular Carcinoma Provides Diagnostic and Therapeutic Opportunities , 2018, Oxidative medicine and cellular longevity.

[13]  Aristeidis E. Boukouris,et al.  Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription. , 2016, Trends in biochemical sciences.

[14]  Hong Chen,et al.  Elevated histone acetylations in Müller cell contribute to inflammation: A novel inhibitory effect of minocycline , 2012, Glia.

[15]  Mao Mao,et al.  Next generation sequencing reveals genetic landscape of hepatocellular carcinomas. , 2013, Cancer letters.

[16]  A. Harris,et al.  How cancer metabolism is tuned for proliferation and vulnerable to disruption , 2012, Nature.

[17]  Sharmila Patel,et al.  Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease. , 2009, Current topics in medicinal chemistry.

[18]  J. Locasale.  Serine, glycine and one-carbon units: cancer metabolism in full circle , 2013, Nature Reviews Cancer.

[19]  G. Yoon,et al.  Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer , 2015, Oncology.

[20]  D. Sabatini,et al.  Cancer Cell Metabolism: Warburg and Beyond , 2008, Cell.

[21]  Chengyu Liu,et al.  Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy , 2017, Autophagy.

[22]  M. Azodi,et al.  Glyceraldehyde-3-phosphate dehydrogenase binds to the AU-Rich 3' untranslated region of colony-stimulating factor-1 (CSF-1) messenger RNA in human ovarian cancer cells: possible role in CSF-1 posttranscriptional regulation and tumor phenotype. , 2005, Cancer research.

[23]  Š. Polák,et al.  Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. , 2016, Acta histochemica.

[24]  R. Petersen,et al.  DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding , 2014, International Journal of Obesity.

[25]  Darren R. Williams,et al.  Chemical targeting of GAPDH moonlighting function in cancer cells reveals its role in tubulin regulation. , 2014, Chemistry & biology.

[26]  G. Minuk,et al.  Comparison of glyceraldehyde‐3‐phosphate dehydrogenase and 28S‐ribosomal RNA gene expression in human hepatocellular carcinoma , 1996, Hepatology.

[27]  M. Ziegler,et al.  The NAD metabolome — a key determinant of cancer cell biology , 2012, Nature Reviews Cancer.

[28]  R. Winn,et al.  The soft agar colony formation assay. , 2014, Journal of visualized experiments : JoVE.

[29]  S. Shao,et al.  Elevated GAPDH expression is associated with the proliferation and invasion of lung and esophageal squamous cell carcinomas , 2015, Proteomics.

[30]  K. Greulich,et al.  Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. , 2004, Genomics.

[31]  Yunhong Zha,et al.  The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. , 2013, Cell metabolism.

[32]  Abhishek K. Jha,et al.  Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. , 2013, Cancer cell.

[33]  D. Santamaría,et al.  Cyclins and CDKS in development and cancer: lessons from genetically modified mice. , 2006, Frontiers in bioscience : a journal and virtual library.

[34]  K. Morten,et al.  The Warburg effect: 80 years on , 2016, Biochemical Society transactions.

[35]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[36]  N. Seidler.  Basic biology of GAPDH. , 2013, Advances in experimental medicine and biology.

[37]  D. Gutmann,et al.  Astrocyte-specific expression of CDK4 is not sufficient for tumor formation, but cooperates with p53 heterozygosity to provide a growth advantage for astrocytes in vivo , 2002, Oncogene.

[38]  J. Geschwind,et al.  Human hepatocellular carcinoma in a mouse model: assessment of tumor response to percutaneous ablation by using glyceraldehyde-3-phosphate dehydrogenase antagonists. , 2012, Radiology.

[39]  John R Yates,et al.  Forward chemical genetic approach identifies new role for GAPDH in insulin signaling. , 2007, Nature chemical biology.

[40]  H. Timmers,et al.  Histone lysine methylation and demethylation pathways in cancer. , 2011, Biochimica et biophysica acta.

[41]  Hong Chen,et al.  Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets. , 2012, Journal of hepatology.

[42]  R. Petersen,et al.  MPHOSPH1: a potential therapeutic target for hepatocellular carcinoma. , 2014, Cancer research.

[43]  R. Petersen,et al.  Overexpression of glyceraldehyde 3‐phosphate dehydrogenase prevents neurovascular degeneration after retinal injury , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[44]  K. Vousden,et al.  Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. , 2014, Cell reports.

[45]  Bing-jun Ma,et al.  Coffee components inhibit amyloid formation of human islet amyloid polypeptide in vitro: possible link between coffee consumption and diabetes mellitus. , 2011, Journal of agricultural and food chemistry.

[46]  Gregory Stephanopoulos,et al.  Amplification of phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis , 2012, BMC Proceedings.

[47]  Z. Hall.  Cancer , 1906, The Hospital.

[48]  Y. Muto,et al.  Glycolytic flux controls d-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes , 2015, Proceedings of the National Academy of Sciences.

[49]  B. Gao,et al.  STAT proteins - key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. , 2012, Journal of hepatology.

[50]  I. Amelio,et al.  Serine and glycine metabolism in cancer☆ , 2014, Trends in biochemical sciences.

[51]  J. Workman,et al.  Serine and SAM Responsive Complex SESAME Regulates Histone Modification Crosstalk by Sensing Cellular Metabolism. , 2015, Molecular cell.