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.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Wang Q,Zheng J,Zou JX,Xu J,Han F,Xiang S,Liu P,Chen HW,Wang Jdoi
10.1016/j.cbi.2020.108965subject
Has Abstractpub_date
2020-02-01 00:00:00pages
108965eissn
0009-2797issn
1872-7786pii
S0009-2797(19)31682-5journal_volume
317pub_type
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