{"title":"E26转化特异性转录因子3打破了平衡:抑制原肌球蛋白2以促进卵巢癌中yes相关蛋白1驱动的顺铂耐药。","authors":"Yan Wang, Zhujing Xu, Chanfeng He, Huiling Qu, Yiting Yang, Yongzheng Lu, Xiaojuan Dong","doi":"10.1097/CAD.0000000000001761","DOIUrl":null,"url":null,"abstract":"<p><p>Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":""},"PeriodicalIF":2.2000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"E26 transformation-specific transcription factor 3 tips the balance: repressing tropomyosin 2 to fuel Yes-associated protein 1-driven cisplatin resistance in ovarian cancer.\",\"authors\":\"Yan Wang, Zhujing Xu, Chanfeng He, Huiling Qu, Yiting Yang, Yongzheng Lu, Xiaojuan Dong\",\"doi\":\"10.1097/CAD.0000000000001761\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.</p>\",\"PeriodicalId\":7969,\"journal\":{\"name\":\"Anti-Cancer Drugs\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Anti-Cancer Drugs\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/CAD.0000000000001761\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anti-Cancer Drugs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/CAD.0000000000001761","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
顺铂耐药仍然是卵巢癌治疗的主要挑战,严重限制了治疗效果。本研究旨在探讨E26转化特异性转录因子3 (ELK3)在顺铂耐药中的作用,并阐明涉及原肌球蛋白2 (TPM2)-Yes-associated protein 1 (YAP1)信号轴的潜在分子机制。通过沉默ELK3和TPM2联合顺铂治疗,评估ELK3和TPM2对卵巢癌细胞顺铂敏感性的调节作用。ELK3和TPM2启动子之间的相互作用通过染色质免疫沉淀和双荧光素酶报告基因检测得到验证。采用Western blotting检测DNA损伤标记γ -组蛋白H2AX和YAP1的表达,探讨TPM2在elk3介导的信号传导和药物反应中的作用。顺铂治疗显著提高ELK3表达。敲低ELK3通过抑制细胞增殖、促进细胞凋亡和增加DNA损伤来增强顺铂敏感性。从机制上讲,ELK3直接结合到TPM2的启动子区域并抑制其转录。TPM2的下调随后导致YAP1信号通路的激活增加。救援实验表明,沉默TPM2可逆转ELK3敲低的化学增敏作用。这些发现强调了ELK3/TPM2/YAP1轴是顺铂耐药的关键调节因子。通过抑制TPM2并随后激活YAP1信号,我们的研究发现ELK3是卵巢癌顺铂耐药的关键转录抑制因子。
E26 transformation-specific transcription factor 3 tips the balance: repressing tropomyosin 2 to fuel Yes-associated protein 1-driven cisplatin resistance in ovarian cancer.
Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.
期刊介绍:
Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.