S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis
机构：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China[2]Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA[3]Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA[4]Shantou University Medical College, No. 22 Xinling Road, Shantou, China[5]Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, PR China中山大学附属第二医院[6]Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, PR China广东省中医院[7]National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China
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.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81572925, 81872891]; Guangdong Natural Science Funds for Distinguished Young Scholar [2019B151502016]; science and Technology Planning Project of Guangdong Province [2017A050506042]; National Institutes of Health (NIH, USA)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 DK060019, R01 CA224900]
第一作者机构：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China
共同第一作者：
通讯作者：
通讯机构：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China[2]Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA[3]Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, USA[7]National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China[*1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China.[*2]Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA.
推荐引用方式(GB/T 7714)：
Wang Qianqian,Zheng Jianwei,Zou June X.,et al.S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis[J].CHEMICO-BIOLOGICAL INTERACTIONS.2020,317:doi:10.1016/j.cbi.2020.108965.
APA：
Wang, Qianqian,Zheng, Jianwei,Zou, June X.,Xu, Jianzhen,Han, Fanghai...&Wang, Junjian.(2020).S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis.CHEMICO-BIOLOGICAL INTERACTIONS,317,
MLA：
Wang, Qianqian,et al."S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis".CHEMICO-BIOLOGICAL INTERACTIONS 317.(2020)
