S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis

Qianqian Wang, Jianwei Zheng, June X Zou, Jianzhen Xu, Fanghai Han, Songtao Xiang, Peiqing Liu, Hong Wu Chen, Junjian Wang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer cells and that NSD2 is a potential biomarker of tamoxifen resistant breast cancer. Here, we found that DZNep, an indirect inhibitor of histone methyltransferases, potently induces the degradation of NSD2 protein and inhibits the expression of NSD2 target genes (HK2, G6PD, GLUT1 and TIGAR) involved in the pentose phosphate pathway (PPP). DZNep treatment of tamoxifen-resistant breast cancer cells and xenograft tumors also strongly inhibits tumor growth and the cancer cell survival through decreasing cell production of NADPH and glutathione (GSH) and invoking elevated ROS to cause apoptosis. These findings suggest that DZNep-like agents can be developed to target NSD2 histone methyltransferase for effective treatment of tamoxifen-resistant breast cancer.

Original languageEnglish (US)
Article number108965
JournalChemico-Biological Interactions
Volume317
DOIs
StatePublished - Feb 1 2020

Keywords

  • Breast cancer
  • DZNep
  • NSD2
  • Tamoxifen resistance

ASJC Scopus subject areas

  • Toxicology

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