Anaplastic thyroid cancer (ATC) is a highly lethal malignancy characterized by rapid progression and therapeutic resistance. This study uncovers the pivotal role of extracellular matrix (ECM) stiffness in driving ATC aggressiveness through mechanotransduction mediated by the Integrin α6β4/Focal Adhesion Kinase (FAK) axis. By engineering collagen-coated polyacrylamide hydrogels with tunable rigidity, we demonstrated that high ECM stiffness (60 kPa) markedly enhanced ATC cell proliferation, clonogenicity, migration, and invasion. Mechanistically, stiff matrices induced cytoskeletal reorganization, activated RhoA/Rac1/Cdc42 signaling, and upregulated Integrin α6β4-FAK pathway components, as validated by transcriptomic, proteomic, and functional assays. Pharmacological inhibition of FAK reversed stiffness-dependent tumor-promoting effects in vitro. In vivo, mice injected with tumor cells pre-cultured on high-stiffness ECM-mimicking hydrogels exhibited accelerated subcutaneous tumor growth and increased lung metastatic burden, which were significantly attenuated by FAK-targeted therapy. These findings establish ECM stiffness as a biomechanical determinant of ATC progression and metastasis, offering novel insights into microenvironment-driven malignancy and highlighting FAK as a promising therapeutic target to disrupt mechanosignaling in ATC.
{"title":"Matrix stiffness-driven cytoskeletal remodeling and tumor progression in anaplastic thyroid cancer via integrin-focal adhesion kinase signaling","authors":"Chenyao Li, Yingying Sun, Xu Shan, Tianxue Yang, Guang Chen","doi":"10.1038/s41388-025-03674-9","DOIUrl":"10.1038/s41388-025-03674-9","url":null,"abstract":"Anaplastic thyroid cancer (ATC) is a highly lethal malignancy characterized by rapid progression and therapeutic resistance. This study uncovers the pivotal role of extracellular matrix (ECM) stiffness in driving ATC aggressiveness through mechanotransduction mediated by the Integrin α6β4/Focal Adhesion Kinase (FAK) axis. By engineering collagen-coated polyacrylamide hydrogels with tunable rigidity, we demonstrated that high ECM stiffness (60 kPa) markedly enhanced ATC cell proliferation, clonogenicity, migration, and invasion. Mechanistically, stiff matrices induced cytoskeletal reorganization, activated RhoA/Rac1/Cdc42 signaling, and upregulated Integrin α6β4-FAK pathway components, as validated by transcriptomic, proteomic, and functional assays. Pharmacological inhibition of FAK reversed stiffness-dependent tumor-promoting effects in vitro. In vivo, mice injected with tumor cells pre-cultured on high-stiffness ECM-mimicking hydrogels exhibited accelerated subcutaneous tumor growth and increased lung metastatic burden, which were significantly attenuated by FAK-targeted therapy. These findings establish ECM stiffness as a biomechanical determinant of ATC progression and metastasis, offering novel insights into microenvironment-driven malignancy and highlighting FAK as a promising therapeutic target to disrupt mechanosignaling in ATC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 6","pages":"690-702"},"PeriodicalIF":7.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03674-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-28DOI: 10.1038/s41388-025-03598-4
Wen-Ya Wu, Yun-Song Yang, Lisa Andriani, Yi-Fan Xie, Gen-Hong Di, Zhi-Ming Shao, Jun-Jie Li
Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and immunohistochemical (IHC) staining of biological samples from patients in the CBCSG010 clinical trial who were randomized to receive adjuvant docetaxel-anthracycline-based chemotherapy with or without capecitabine. We find that patients with a better prognosis in the capecitabine group exhibited an immune-inflamed microenvironment and upregulation of interferon pathways. Moreover, we identify interferon-related TANK-binding kinase 1-binding protein 1 (TBKBP1) as the key gene involved in capecitabine resistance. We uncover that TBKBP1 promotes capecitabine resistance through impairment of activated immune cells infiltration in vivo. Mechanistically, TBKBP1 negatively regulates type I interferon pathway activated by capecitabine treatment, by promoting autophagy-mediated protein degradation of TANK binding kinase 1 (TBK1). In summary, our study implicates TBKBP1 in mediating capecitabine resistance and may serve as a potential therapeutic target for the treatment of TNBC.
卡培他滨已被广泛用于治疗早期三阴性乳腺癌（TNBC）患者；然而，这种耐药性限制了它的治疗潜力。在这里，我们对CBCSG010临床试验患者的生物样本进行了多组学数据分析和免疫组织化学（IHC）染色，这些患者被随机分配接受以多西他赛-蒽环类药物为基础的辅助化疗，加或不加卡培他滨。我们发现卡培他滨组预后较好的患者表现出免疫炎症微环境和干扰素通路上调。此外，我们发现干扰素相关的TANK-binding kinase 1-binding protein 1 （TBKBP1）是参与卡培他滨耐药的关键基因。我们发现TBKBP1通过损害体内活化的免疫细胞浸润来促进卡培他滨耐药性。从机制上讲，TBKBP1通过促进自噬介导的TANK结合激酶1 （TBK1）的蛋白降解，负性调节卡培他滨治疗激活的I型干扰素途径。总之，我们的研究提示TBKBP1介导卡培他滨耐药，并可能作为治疗TNBC的潜在治疗靶点。
{"title":"TBKBP1 induces capecitabine resistance through negative regulation of type I interferon pathway in triple-negative breast cancer","authors":"Wen-Ya Wu, Yun-Song Yang, Lisa Andriani, Yi-Fan Xie, Gen-Hong Di, Zhi-Ming Shao, Jun-Jie Li","doi":"10.1038/s41388-025-03598-4","DOIUrl":"10.1038/s41388-025-03598-4","url":null,"abstract":"Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and immunohistochemical (IHC) staining of biological samples from patients in the CBCSG010 clinical trial who were randomized to receive adjuvant docetaxel-anthracycline-based chemotherapy with or without capecitabine. We find that patients with a better prognosis in the capecitabine group exhibited an immune-inflamed microenvironment and upregulation of interferon pathways. Moreover, we identify interferon-related TANK-binding kinase 1-binding protein 1 (TBKBP1) as the key gene involved in capecitabine resistance. We uncover that TBKBP1 promotes capecitabine resistance through impairment of activated immune cells infiltration in vivo. Mechanistically, TBKBP1 negatively regulates type I interferon pathway activated by capecitabine treatment, by promoting autophagy-mediated protein degradation of TANK binding kinase 1 (TBK1). In summary, our study implicates TBKBP1 in mediating capecitabine resistance and may serve as a potential therapeutic target for the treatment of TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 6","pages":"703-714"},"PeriodicalIF":7.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03598-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-24DOI: 10.1038/s41388-025-03636-1
Hejer Dhahri, Kin H. Lau, Wesley N. Saintilnord, Elisson Lopes, Hannah N. Damico, Youssef A. Hegazy, Flavio R. Palma, Daniël P. Melters, Darrell P. Chandler, Yamini Dalal, Jonathan D. Licht, Marcelo G. Bonini, Yvonne N. Fondufe-Mittendorf
Histones scaffold genomic DNA and regulate access to the transcriptional machinery. However, naturally occurring histone variants can alter histone-DNA interactions, DNA and histone modifications, and the chromatin interactome. Hence, alterations in histone variant deposition can disrupt chromatin, and are increasingly recognized as a way to trigger various disease, including cancer. While significant attention has been placed on the biochemical and functional roles of H2A, H3, and H4 histone variants, the variants of H2B remain largely understudied. Here, we show that H2B variants are dysregulated in breast cancer and that certain variants are associated with specific breast cancer subtypes. HIST1H2BO overexpression (in particular) is more common in Asian, African American/Black, and young female populations and is associated with a worse prognosis. In vitro studies show that H2B1O compacts nucleosome structure. Incorporating H2B1O into chromatin activates pro-inflammatory and oncogenic pathways, induces epithelial-to-mesenchymal transition (EMT), and generates resistance to first-line chemotherapeutic agents. Thus, H2B1O acts much like an onco-histone, with H2B variant expression being a prognostic biomarker for breast cancer and a potential new target for drug therapies to enhance treatment efficacy.
{"title":"Single amino-acid differences define H2B variants and modify chromatin accessibility to induce EMT in breast cancer","authors":"Hejer Dhahri, Kin H. Lau, Wesley N. Saintilnord, Elisson Lopes, Hannah N. Damico, Youssef A. Hegazy, Flavio R. Palma, Daniël P. Melters, Darrell P. Chandler, Yamini Dalal, Jonathan D. Licht, Marcelo G. Bonini, Yvonne N. Fondufe-Mittendorf","doi":"10.1038/s41388-025-03636-1","DOIUrl":"10.1038/s41388-025-03636-1","url":null,"abstract":"Histones scaffold genomic DNA and regulate access to the transcriptional machinery. However, naturally occurring histone variants can alter histone-DNA interactions, DNA and histone modifications, and the chromatin interactome. Hence, alterations in histone variant deposition can disrupt chromatin, and are increasingly recognized as a way to trigger various disease, including cancer. While significant attention has been placed on the biochemical and functional roles of H2A, H3, and H4 histone variants, the variants of H2B remain largely understudied. Here, we show that H2B variants are dysregulated in breast cancer and that certain variants are associated with specific breast cancer subtypes. HIST1H2BO overexpression (in particular) is more common in Asian, African American/Black, and young female populations and is associated with a worse prognosis. In vitro studies show that H2B1O compacts nucleosome structure. Incorporating H2B1O into chromatin activates pro-inflammatory and oncogenic pathways, induces epithelial-to-mesenchymal transition (EMT), and generates resistance to first-line chemotherapeutic agents. Thus, H2B1O acts much like an onco-histone, with H2B variant expression being a prognostic biomarker for breast cancer and a potential new target for drug therapies to enhance treatment efficacy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 6","pages":"669-689"},"PeriodicalIF":7.3,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03636-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1038/s41388-026-03677-0
Bangting Wang, Shijie Zhang, Yumeng Guo, Wenqing Gao, Hao Wu, Jiankun Wang, Yan Wang, Chunming Tang, Li Liu
{"title":"Correction: CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis","authors":"Bangting Wang, Shijie Zhang, Yumeng Guo, Wenqing Gao, Hao Wu, Jiankun Wang, Yan Wang, Chunming Tang, Li Liu","doi":"10.1038/s41388-026-03677-0","DOIUrl":"10.1038/s41388-026-03677-0","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"664-666"},"PeriodicalIF":7.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03677-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1038/s41388-026-03678-z
L. Y. Lin, L. M. Du, K. Cao, Y. Huang, P. F. Yu, L. Y. Zhang, F. Y. Li, Y. Wang, Y. F. Shi
{"title":"Correction: Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities","authors":"L. Y. Lin, L. M. Du, K. Cao, Y. Huang, P. F. Yu, L. Y. Zhang, F. Y. Li, Y. Wang, Y. F. Shi","doi":"10.1038/s41388-026-03678-z","DOIUrl":"10.1038/s41388-026-03678-z","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"663-663"},"PeriodicalIF":7.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03678-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1038/s41388-026-03676-1
Jing Sun, Xin Cai, Mingo M. H. Yung, Wei Zhou, Jing Li, Yi Zhang, Zhuqing Li, Stephanie S. Liu, Annie N. Y. Cheung, Hextan Y. S. Ngan, Yiliang Li, Zhijun Dai, Yan Kai, Alexandros Tzatsos, Weiqun Peng, David W. Chan, Wenge Zhu
{"title":"Retraction Note: miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer","authors":"Jing Sun, Xin Cai, Mingo M. H. Yung, Wei Zhou, Jing Li, Yi Zhang, Zhuqing Li, Stephanie S. Liu, Annie N. Y. Cheung, Hextan Y. S. Ngan, Yiliang Li, Zhijun Dai, Yan Kai, Alexandros Tzatsos, Weiqun Peng, David W. Chan, Wenge Zhu","doi":"10.1038/s41388-026-03676-1","DOIUrl":"10.1038/s41388-026-03676-1","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"668-668"},"PeriodicalIF":7.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03676-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1038/s41388-026-03675-2
C. L. Wu, L. Qiang, W. Han, M. Ming, B. Viollet, Y. Y. He
{"title":"Editorial Expression of Concern: Role of AMPK in UVB-induced DNA damage repair and growth control","authors":"C. L. Wu, L. Qiang, W. Han, M. Ming, B. Viollet, Y. Y. He","doi":"10.1038/s41388-026-03675-2","DOIUrl":"10.1038/s41388-026-03675-2","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"667-667"},"PeriodicalIF":7.3,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03675-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41388-025-03672-x
Jasper H.L.T. van Genugten, Dean A. Fennell, Paul Baas
Mesothelioma is an aggressive cancer that is often characterized by loss of the BRCA1-associated protein 1 (BAP1) tumor suppressor gene. This alteration typically occurs as an early clonal event in mesothelioma development, making it a promising candidate for both diagnostic and therapeutic applications. Functionally, BAP1 regulates gene expression through interactions with Polycomb-group complexes, and it plays roles in various other cellular processes including DNA repair, replication stress, and cell metabolism. While preclinical research has identified multiple potential vulnerabilities in BAP1-deficient tumors—including sensitivity to EZH2-, HDAC-, PARP-, and FGFR-inhibitors—translating these findings to the clinic remains a challenge. In this review, we provide a comprehensive overview of BAP1’s molecular functions in mesothelioma, with a focus on their translation into clinical therapeutics for this hard-to-treat malignancy.
{"title":"BAP1-loss in mesothelioma: molecular mechanisms and clinical opportunities","authors":"Jasper H.L.T. van Genugten, Dean A. Fennell, Paul Baas","doi":"10.1038/s41388-025-03672-x","DOIUrl":"10.1038/s41388-025-03672-x","url":null,"abstract":"Mesothelioma is an aggressive cancer that is often characterized by loss of the BRCA1-associated protein 1 (BAP1) tumor suppressor gene. This alteration typically occurs as an early clonal event in mesothelioma development, making it a promising candidate for both diagnostic and therapeutic applications. Functionally, BAP1 regulates gene expression through interactions with Polycomb-group complexes, and it plays roles in various other cellular processes including DNA repair, replication stress, and cell metabolism. While preclinical research has identified multiple potential vulnerabilities in BAP1-deficient tumors—including sensitivity to EZH2-, HDAC-, PARP-, and FGFR-inhibitors—translating these findings to the clinic remains a challenge. In this review, we provide a comprehensive overview of BAP1’s molecular functions in mesothelioma, with a focus on their translation into clinical therapeutics for this hard-to-treat malignancy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"593-602"},"PeriodicalIF":7.3,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41388-025-03662-z
Wanqing Xie, Qi Chu, Lourdes Brea, Guihua Zeng, Yuan Wang, Xiaodong Lu, Mohan Zheng, Corinne R. Ley, Zhiquan Lei, Hongshun Shi, Joshua L. Zhu, Lihu Gong, M. Cynthia Martin, Xianglin Shi, Galina Gritsina, Arabela A. Grigorescu, Hana Chandonnet, Xin Liu, Jonathan C. Zhao, Gary E. Schiltz, Jindan Yu
Enhancer of Zeste Homolog 2 (EZH2) is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). It catalyzes H3K27 methylation for epigenetic silencing of tumor suppressors and critically drives prostate cancer (PCa) progression. However, inhibitors of EZH2 catalytic function (EZH2i), such as EPZ-6438, showed limited efficacy in PCa. Here, we designed and developed a series of VHL-based proteolysis-targeting chimera (PROTAC) degraders of EZH2 using EPZ-6438 as a ligand and identified PROTAC-6272 as a lead compound. PROTAC-6272 effectively degraded EZH2 and other PRC2 subunits across diverse PCa cell lines. However, PROTAC-6272 and other similar EZH2i-based PROTACs were consistently unable to decrease androgen receptor (AR), a gene that is directly activated by solo EZH2. Mechanistically, EZH2 PROTACs failed to degrade EZH2 coactivators, such as p300, due to their inability to engage EZH2 outside of the PRC2 complex. Nevertheless, PROTAC-6272 exhibited anti-proliferative activities superior to EPZ-6438 in some PCa models, wherein it induced p21 expression and cellular senescence by disrupting a methylation-independent PRC2 function. In summary, while EZH2i-based PROTACs failed to target the PRC2-independent functions of EZH2, they confer added benefits over EPZ-6438 by abolishing a polycomb-dependent but methylation-independent function of EZH2, offering therapeutic advantages in some PCa.
{"title":"EZH2 PROTACs outperform catalytic inhibitors in prostate cancer by targeting a methylation-independent function of PRC2","authors":"Wanqing Xie, Qi Chu, Lourdes Brea, Guihua Zeng, Yuan Wang, Xiaodong Lu, Mohan Zheng, Corinne R. Ley, Zhiquan Lei, Hongshun Shi, Joshua L. Zhu, Lihu Gong, M. Cynthia Martin, Xianglin Shi, Galina Gritsina, Arabela A. Grigorescu, Hana Chandonnet, Xin Liu, Jonathan C. Zhao, Gary E. Schiltz, Jindan Yu","doi":"10.1038/s41388-025-03662-z","DOIUrl":"10.1038/s41388-025-03662-z","url":null,"abstract":"Enhancer of Zeste Homolog 2 (EZH2) is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). It catalyzes H3K27 methylation for epigenetic silencing of tumor suppressors and critically drives prostate cancer (PCa) progression. However, inhibitors of EZH2 catalytic function (EZH2i), such as EPZ-6438, showed limited efficacy in PCa. Here, we designed and developed a series of VHL-based proteolysis-targeting chimera (PROTAC) degraders of EZH2 using EPZ-6438 as a ligand and identified PROTAC-6272 as a lead compound. PROTAC-6272 effectively degraded EZH2 and other PRC2 subunits across diverse PCa cell lines. However, PROTAC-6272 and other similar EZH2i-based PROTACs were consistently unable to decrease androgen receptor (AR), a gene that is directly activated by solo EZH2. Mechanistically, EZH2 PROTACs failed to degrade EZH2 coactivators, such as p300, due to their inability to engage EZH2 outside of the PRC2 complex. Nevertheless, PROTAC-6272 exhibited anti-proliferative activities superior to EPZ-6438 in some PCa models, wherein it induced p21 expression and cellular senescence by disrupting a methylation-independent PRC2 function. In summary, while EZH2i-based PROTACs failed to target the PRC2-independent functions of EZH2, they confer added benefits over EPZ-6438 by abolishing a polycomb-dependent but methylation-independent function of EZH2, offering therapeutic advantages in some PCa.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"636-649"},"PeriodicalIF":7.3,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03662-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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