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Author Spotlight: Epigenetic Modifications and Metabolic Rewiring as Targets for Cancer Therapy
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Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of

Junjian Wang1, Zhijian Duan1, Zoann Nugent2

  • 1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States.

Cancer Letters
|May 11, 2016
PubMed

Insights

The histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer by epigenetically upregulating glucose metabolism enzymes. This suggests NSD2 as a therapeutic target for endocrine-resistant breast cancer.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Metabolism

Background:

  • Metabolic reprogramming, including the Warburg effect, is a hallmark of cancer.
  • Molecular mechanisms of metabolic alterations contributing to therapeutic resistance remain unclear.
  • Endocrine resistance is a significant challenge in breast cancer treatment.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying metabolic alterations in tamoxifen-resistant breast cancer.
  • To identify potential therapeutic targets for endocrine-resistant breast cancer.

Main Methods:

  • Gene expression profiling of tamoxifen-resistant breast cancer cell lines and tumors.
  • Immunohistochemistry (IHC) to assess NSD2 protein levels.
  • Functional studies involving ectopic expression of NSD2 and its mutants in cell models and xenografts.
  • Analysis of glucose metabolic enzyme gene expression and pathway activity (glycolysis, pentose phosphate pathway).

Main Results:

  • NSD2 (histone H3K36 methyltransferase) expression is elevated in tamoxifen-resistant breast cancer.
  • NSD2 overexpression correlates with disease recurrence and poor survival.
  • NSD2 drives endocrine resistance by methylating H3K36me2 at promoters of key metabolic enzymes, including HK2 and G6PD.
  • NSD2 upregulates the pentose phosphate pathway (PPP), increasing NADPH and reducing reactive oxygen species (ROS) in resistant cells.

Conclusions:

  • NSD2 epigenetically activates key glucose metabolic enzymes, contributing to tamoxifen resistance in breast cancer.
  • NSD2 plays a crucial role in metabolic reprogramming associated with therapeutic resistance.
  • NSD2 is a potential therapeutic target for overcoming endocrine resistance in breast cancer.
Keywords:
Histone methyltransferaseMetabolismNSD2Pentose phosphate pathwayTamoxifen resistance

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