The combination of BET and METTL3 inhibitors elicits synergistic antitumor effects in ovarian cancer cells via reducing SP1 and BCL-2 expression
文献类型：期刊论文
| 作者 | Ou, Ying-Jie1,2; Liu, Ben-Jin1,2; Xuan, Yi-Fei1,2; Bao, Xu-Bin2; Huan, Xia-Juan2; Song, Shan-Shan2; Su, Ai-Ling1,2; Miao, Ze-Hong1,2; Wang, Ying-Qing1,2
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| 刊名 | LIFE SCIENCES
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| 出版日期 | 2025-05-01 |
| 卷号 | 368页码:14 |
| 关键词 | BET inhibitor METTL3 inhibitor Combination therapy SP1 BCL-2 |
| ISSN号 | 0024-3205 |
| DOI | 10.1016/j.lfs.2025.123505 |
| 英文摘要 | Ovarian cancer (OC) remains a major health threat to woman despite treatment advances. New therapeutic strategies are demanded to persistently explored. In this study, we found that inhibitors of bromodomain and extra-Terminal domain (BET) and methyltransferase-like 3 (METTL3) exerted synergistic proliferative inhibition in different OC cell lines. In vitro synergism was translated into in vivo antitumor activity through the combination of BET inhibitor HJP-178 and METTL3 inhibitor STM2457. Mechanistically, this combination mainly enhanced apoptosis rather than affecting cell cycle arrest. Furthermore, it was revealed that HJP-178 decreased the transcription of Specificity protein 1 (SP1) while STM2457 lowered the N6-methyladenosine (m6A) levels of SP1 mRNA. Consequently, their combination synergistically reduces SP1 RNA and protein levels through both transcriptional and post-transcriptional modifications. Further exploration demonstrated that inhibiting SP1 directly downregulates the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), activating the caspase-mediated apoptotic pathway and triggering programmed cell death. Importantly, SP1 overexpression significantly reducing the apoptosis induction and proliferation inhibition induced by the combination. Similarly, BCL-2 overexpression mimicked the effects of increased SP1. These results demonstrate the critical roles of SP1 and BCL-2 in the synergistic antitumor activity between BET and METTL3 inhibitors. Collectively, our findings broaden the potential applications of both drug types and present a promising therapeutic approach for OC, warranting further investigation in clinical settings. |
| WOS关键词 | EPITHELIAL OVARIAN ; BROMODOMAIN ; CARBOPLATIN ; PROGRESSION ; PACLITAXEL |
| 资助项目 | National Natural Science Foundation of China[82073865] ; National Natural Science Foundation of China[81773764] ; Science and Technology Commission of Shanghai Municipality[20ZR1468100] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231010] ; State Key Laboratory of Drug Research |
| WOS研究方向 | Research & Experimental Medicine ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001435858000001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316496]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wang, Ying-Qing |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ou, Ying-Jie,Liu, Ben-Jin,Xuan, Yi-Fei,et al. The combination of BET and METTL3 inhibitors elicits synergistic antitumor effects in ovarian cancer cells via reducing SP1 and BCL-2 expression[J]. LIFE SCIENCES,2025,368:14. |
| APA | Ou, Ying-Jie.,Liu, Ben-Jin.,Xuan, Yi-Fei.,Bao, Xu-Bin.,Huan, Xia-Juan.,...&Wang, Ying-Qing.(2025).The combination of BET and METTL3 inhibitors elicits synergistic antitumor effects in ovarian cancer cells via reducing SP1 and BCL-2 expression.LIFE SCIENCES,368,14. |
| MLA | Ou, Ying-Jie,et al."The combination of BET and METTL3 inhibitors elicits synergistic antitumor effects in ovarian cancer cells via reducing SP1 and BCL-2 expression".LIFE SCIENCES 368(2025):14. |
入库方式： OAI收割
来源：上海药物研究所
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