Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

Junjian Wang, Zhijian Duan, Zoann Nugent, June X Zou, Alexander D Borowsky, Yanhong Zhang, Clifford G Tepper, Jian-Jian Li, Oliver Fiehn, Jianzhen Xu, Hsing-Jien Kung, Leigh C. Murphy, Hongwu Chen

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalCancer Letters
Volume378
Issue number2
DOIs
StatePublished - Aug 10 2016

Keywords

  • Histone methyltransferase
  • Metabolism
  • NSD2
  • Pentose phosphate pathway
  • Tamoxifen resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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