Pan-cancer analysis of G6PD carcinogenesis in human tumors.

Glucose-6-phosphate dehydrogenase (G6PD) is involved in the catalytic pentose phosphate pathway (PPP), which is closely related to energy metabolism. G6PD plays a crucial role in many types of cancer, but the specific molecular mechanisms of G6PD in cancer remain unclear. Therefore, we investigated the potential oncogenic role of G6PD in various tumors based on The Cancer Genome Atlas (TCGA), the cBioPortal datasets, the University of California Santa Cruz (UCSC) Xena browser and the UALCAN-based online tool. G6PD was highly expressed in several cancer tissues (hepatocellular carcinoma, glioma, and breast cancer) compared with normal tissues and was significantly associated with poor prognosis of hepatocellular carcinoma, clear cell renal cell carcinoma, and breast cancer. Promoter methylation levels of G6PD were lower in Bladder Urothelial Carcinoma (BLCA) (P = 2.77e-02), breast invasive carcinoma (BRCA) (P = 1.62e-12), kidney renal clear cell carcinoma (KIRC) (P = 4.23e-02), kidney renal papillary cell carcinoma (KIRP) (P = 2.64e-03), liver hepatocellular carcinoma (LIHC) (P = 1.76e-02), stomach adenocarcinoma (STAD) (P = 3.50e-02), and testicular germ cell tumors (TGCT) (P = 1.62e-12) and higher in prostate adenocarcinoma (PRAD) (P = 1.81e-09) and uterine corpus endometrial carcinoma (UCEC) (P = 2.96e-04) compared with corresponding normal tissue samples. G6PD expression was positively correlated with the infiltration level of immune cells in most tumors, suggesting that G6PD may be involved in tumor immune infiltration. In addition, the functional mechanism of G6PD also involves "Carbon metabolism", "Glycolysis/Gluconeogenesis", "Pentose phosphate pathway", and "Central carbon pathway metabolism in cancer signaling pathway". This pan-cancer study provides a relatively broad understanding of the oncogenic role of G6PD in various tumors and presents a theoretical basis for the development of G6PD inhibitors as therapeutic drugs for multiple cancers.

[1]  Jong-Hee Chang,et al.  Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres. , 2022, Journal of neuro-oncology.

[2]  B. Liu,et al.  Recent findings in the regulation of G6PD and its role in diseases , 2022, Frontiers in Pharmacology.

[3]  Hao Yang,et al.  A novel tumor-homing TRAIL variant eradicates tumor xenografts of refractory colorectal cancer cells in combination with tumor cell-targeted photodynamic therapy , 2022, Drug delivery.

[4]  P. Philip,et al.  Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets , 2022, Oncogene.

[5]  H. Moon,et al.  Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase , 2022, British Journal of Cancer.

[6]  Huatao Niu,et al.  5-Aza-dC suppresses melanoma progression by inhibiting GAS5 hypermethylation , 2022, Oncology reports.

[7]  Rui Wang,et al.  Synergistic autophagy blockade and VDR signaling activation enhance stellate cell reprogramming in pancreatic ductal adenocarcinoma. , 2022, Cancer letters.

[8]  C. Shi,et al.  Interference With Redox Homeostasis Through a G6PD-Targeting Self-Assembled Hydrogel for the Enhancement of Sonodynamic Therapy in Breast Cancer , 2022, Frontiers in Chemistry.

[9]  C. Braconi,et al.  Metabolic Reprogramming in Cholangiocarcinoma. , 2022, Journal of hepatology.

[10]  Li-Dong Wang,et al.  Long non-coding RNA ZNF667-AS1 retards the development of esophageal squamous cell carcinoma via modulation of microRNA-1290-mediated PRUNE2 , 2022, Translational oncology.

[11]  S. Burley,et al.  mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma , 2022, Theranostics.

[12]  T. Yoneda,et al.  The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer , 2022, Scientific Reports.

[13]  Zhixiang Wu,et al.  Pan-cancer analyses reveal the regulation and clinical outcome association of PCLAF in human tumors , 2022, International journal of oncology.

[14]  Bahar Naghavi Gargari,et al.  Inhibiting the growth of melanoma cells via hTERT gene editing using CRISPR-dCas9-dnmt3a system. , 2022, Gene.

[15]  Shangyi Luo,et al.  Telomere maintenance mechanism dysregulation serves as an early predictor of adjuvant therapy response and a potential therapeutic target in human cancers , 2022, International journal of cancer.

[16]  S. Batra,et al.  Macrophage inhibitory cytokine-1 in cancer: Beyond the cellular phenotype. , 2022, Cancer letters.

[17]  Shengli Liu,et al.  Molecular Characteristics, Clinical Significance, and Cancer Immune Interactions of Angiogenesis-Associated Genes in Gastric Cancer , 2022, Frontiers in Immunology.

[18]  Z. Selamoğlu,et al.  Identification of Macrolepiota procera extract as a novel G6PD inhibitor for the treatment of lung cancer , 2022, Saudi journal of biological sciences.

[19]  C. Shan,et al.  The Multiple Roles of Glucose-6-Phosphate Dehydrogenase in Tumorigenesis and Cancer Chemoresistance , 2022, Life.

[20]  K. Kovar,et al.  Better by design: What to expect from novel CAR-engineered cell therapies? , 2022, Biotechnology advances.

[21]  R. Houlston,et al.  Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis , 2022, International journal of cancer.

[22]  Johann S. Hawe,et al.  Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function , 2022, Nature Genetics.

[23]  J. Rabinowitz,et al.  Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition , 2021, Science advances.

[24]  Hyun-Woo Rhee,et al.  Spatial Regulation of Reactive Oxygen Species via G6PD in Brown Adipocytes Supports Thermogenic Function , 2021, Diabetes.

[25]  Man Xiao,et al.  miR-206-G6PD axis regulates lipogenesis and cell growth in hepatocellular carcinoma cell , 2021, Anti-cancer drugs.

[26]  Kaixian Chen,et al.  Discovery and characterization of a novel glucose-6-phosphate dehydrogenase (G6PD) inhibitor via high-throughput screening. , 2021, Bioorganic & medicinal chemistry letters.

[27]  Ming Sun,et al.  LINC00242/miR-1-3p/G6PD axis regulates Warburg effect and affects gastric cancer proliferation and apoptosis , 2021, Molecular medicine.

[28]  Yuechun Zhu,et al.  G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression , 2020, International journal of medical sciences.

[29]  D. Xie,et al.  NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications , 2020, Signal Transduction and Targeted Therapy.

[30]  Yuechun Zhu,et al.  G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS-MAPK axis pathway , 2020, International journal of oncology.

[31]  X. Ren,et al.  Expression signature, prognosis value, and immune characteristics of Siglec-15 identified by pan-cancer analysis , 2020, Oncoimmunology.

[32]  A. Stern,et al.  Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling , 2019, Redox biology.

[33]  Q. Qi,et al.  4-hydroxyphenylpyruvate dioxygenase promotes lung cancer growth via pentose phosphate pathway (PPP) flux mediated by LKB1-AMPK/HDAC10/G6PD axis , 2019, Cell Death & Disease.

[34]  Zemin Zhang,et al.  GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis , 2019, Nucleic Acids Res..

[35]  Damian Szklarczyk,et al.  STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets , 2018, Nucleic Acids Res..

[36]  Hao Pan,et al.  Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro. , 2018, International journal of oncology.

[37]  M. Miyagishi,et al.  Transcription Factor YY1 Promotes Cell Proliferation by Directly Activating the Pentose Phosphate Pathway. , 2018, Cancer research.

[38]  Hsi-Yuan Huang,et al.  G6PD as a predictive marker for glioma risk, prognosis and chemosensitivity , 2018, Journal of Neuro-Oncology.

[39]  L. Qin,et al.  Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition , 2018, Acta biochimica et biophysica Sinica.

[40]  Steven J. M. Jones,et al.  The Immune Landscape of Cancer , 2018, Immunity.

[41]  Jun S. Liu,et al.  TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. , 2017, Cancer research.

[42]  Russell Bonneville,et al.  Landscape of Microsatellite Instability Across 39 Cancer Types. , 2017, JCO precision oncology.

[43]  Chad J. Creighton,et al.  UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses , 2017, Neoplasia.

[44]  Carlos Caldas,et al.  Patterns of Immune Infiltration in Breast Cancer and Their Clinical Implications: A Gene-Expression-Based Retrospective Study , 2016, PLoS medicine.

[45]  Steven P. Gygi,et al.  Defining the consequences of genetic variation on a proteome-wide scale , 2016, Nature.

[46]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[47]  K. Tomczak,et al.  The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge , 2015, Contemporary oncology.

[48]  N. Hay,et al.  The pentose phosphate pathway and cancer. , 2014, Trends in biochemical sciences.

[49]  P. Jiang,et al.  A critical role of glucose-6-phosphate dehydrogenase in TAp73-mediated cell proliferation , 2013, Cell cycle.

[50]  T. Mak,et al.  TAp73 enhances the pentose phosphate pathway and supports cell proliferation , 2013, Nature Cell Biology.

[51]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[52]  V. Costanzo,et al.  ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair , 2010, The EMBO journal.

[53]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[54]  B. Horecker.  The Pentose Phosphate Pathway , 2002, The Journal of Biological Chemistry.