Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition
文献类型：期刊论文
| 作者 | Yu, Lei1,2; Wang, Ya-fang1; Xiao, Jian1,2; Shen, Qian-qian1; Chi, Shuai-shuai1,2; Gao, Ying-lei1; Lin, Dong-ze1; Ding, Jian1,2,3,4 ; Fang, Yan-fen1,2,3; Chen, Yi1,2,4,5
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2023-05-25 |
| 页码 | 12 |
| ISSN号 | 1671-4083 |
| 关键词 | diffuse large B-cell lymphoma EZH2 TfR-1 GPX4 ferroptosis HH2853 |
| DOI | 10.1038/s41401-023-01097-4 |
| 通讯作者 | Ding, Jian(jding@simm.ac.cn) ; Fang, Yan-fen(yffang@simm.ac.cn) ; Chen, Yi(ychen@simm.ac.cn) |
| 英文摘要 | EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy. |
| WOS关键词 | DRUG-RESISTANCE ; FERROPTOSIS ; DEATH ; METABOLISM ; ACTIVATION |
| 资助项目 | Program of Shanghai Academic Research Leader[22XD1404400] ; Chinese Academy of Sciences[XDA12020233] ; Youth Innovation Promotion Association of Chinese Academy of Sciences[2020281] ; Lingang Laboratory[LG202103-02-05] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | NATURE PUBL GROUP |
| WOS记录号 | WOS:000994118800002 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/306185]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian; Fang, Yan-fen; Chen, Yi |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yu, Lei,Wang, Ya-fang,Xiao, Jian,et al. Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition[J]. ACTA PHARMACOLOGICA SINICA,2023:12. |
| APA | Yu, Lei.,Wang, Ya-fang.,Xiao, Jian.,Shen, Qian-qian.,Chi, Shuai-shuai.,...&Chen, Yi.(2023).Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition.ACTA PHARMACOLOGICA SINICA,12. |
| MLA | Yu, Lei,et al."Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition".ACTA PHARMACOLOGICA SINICA (2023):12. |
入库方式： OAI收割
来源：上海药物研究所
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