title: Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes.
abstract: Metabolic reprogramming such as the aerobic glycolysis or Warburg effect is well recognized as a common feature of tumorigenesis. However, molecular mechanisms underlying metabolic alterations for tumor therapeutic resistance are poorly understood. Through gene expression profiling analysis we found that histone H3K36 methyltransferase NSD2/MMSET/WHSC1 expression was highly elevated in tamoxifen-resistant breast cancer cell lines and clinical tumors. IHC analysis indicated that NSD2 protein overexpression was associated with the disease recurrence and poor survival. Ectopic expression of NSD2 wild type, but not the methylase-defective mutant, drove endocrine resistance in multiple cell models and xenograft tumors. Mechanistically, NSD2 was recruited to and methylated H3K36me2 at the promoters of key glucose metabolic enzyme genes. Its overexpression coordinately up-regulated hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD), two key enzymes of glycolysis and the pentose phosphate pathway (PPP), as well as TP53-induced glycolysis regulatory phosphatase TIGAR. Consequently, NSD2-driven tamoxifen-resistant cells and tumors displayed heightened PPP activity, elevated NADPH production, and reduced ROS level, without significantly altered glycolysis. These results illustrate a coordinated, epigenetic activation of key glucose metabolic enzymes in therapeutic resistance and nominate methyltransferase NSD2 as a potential therapeutic target for endocrine resistant breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Junjian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Duan
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg R3E 0V9, Canada.
authors.forename: Zoann
authors.initials: Z
authors.lastname: Nugent
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: June X
authors.initials: JX
authors.lastname: Zou
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Jian Jian
authors.initials: JJ
authors.lastname: Li
authors.affiliation: UC Davis Genome Center - Metabolomics, University of California, Davis, CA 95616, United States.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Bioinformatics, Shantou University Medical College, Shantou, China.
authors.forename: Jianzhen
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States; UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, CA 95817, United States.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg R3E 0V9, Canada.
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States; UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, CA 95817, United States. Electronic address: hwzchen@ucdavis.edu.
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Chen
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D065150:Cellular Reprogramming; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D013629:Tamoxifen; D009249:NADP; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human
keywords: Histone methyltransferase; Metabolism; NSD2; Pentose phosphate pathway; Tamoxifen resistance