OncogenePub Date : 2025-08-07DOI: 10.1038/s41388-025-03518-6
Jie Tian, Shihui Liu, Yunqing Zhang, Huajie Jia, Wenna Nie, Ran Yang, Mengmeng Ge, Kangdong Liu, Mengqiu Song, Zigang Dong
{"title":"LIMK2 promotes centrosome clustering and cancer progression by activating MST4-mediated phosphorylation of NPM1","authors":"Jie Tian, Shihui Liu, Yunqing Zhang, Huajie Jia, Wenna Nie, Ran Yang, Mengmeng Ge, Kangdong Liu, Mengqiu Song, Zigang Dong","doi":"10.1038/s41388-025-03518-6","DOIUrl":"10.1038/s41388-025-03518-6","url":null,"abstract":"Centrosome amplification, a hallmark of diverse malignancies, enables cancer cell survival through centrosome clustering during mitosis, presenting a promising therapeutic target for selective elimination of cancer cells with supernumerary centrosomes. While the regulatory mechanisms underlying centrosome clustering remain poorly understood, our study identifies LIM kinase 2 (LIMK2) as a critical regulator of this process, demonstrating cancer correlation with tumor progression. Mechanistically, LIMK2 phosphorylates mammalian sterile-20-like kinase 4 (MST4) at threonine 178 (T178), activating its kinase function. Activated MST4 subsequently binds and phosphorylates nucleophosmin 1 (NPM1) at T95, a modification essential for centrosome clustering and tumor cell proliferation. Genetic depletion of NPM1 disrupts centrosome clustering and suppresses malignant growth. In vivo studies revealed that LIMK2 knockout significantly attenuates 4-nitroquinoline-1-oxide (4NQO) induced esophageal tumorigenesis in murine models. Therapeutic targeting of LIMK2 through shRNA-mediated knock down or pharmacological inhibition (CRT0105950) suppresses centrosome clustering by preventing “pseudo-bipolar” spindle formation, inducing mitosis arrest. This centrosome de-clustering promotes multipolar spindle assembly, ultimately triggering apoptotic cell death. Notably, CRT0105950 treatment effectively suppressed cell-derived xenograft tumor growth. Our findings elucidate the pivotal role of the LIMK2/MST4/NPM1 pathway in cancer progression and establish a novel therapeutic paradigm for broad-spectrum anticancer intervention.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3625-3639"},"PeriodicalIF":7.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03518-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799683","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}
OncogenePub Date : 2025-08-07DOI: 10.1038/s41388-025-03531-9
C. Andrieu, D. Taieb, V. Baylot, S. Ettinger, P. Soubeyran, A. De-Thonel, C. Nelson, C. Garrido, A. So, L. Fazli, F. Bladou, M. Gleave, J. L. Iovanna, P. Rocchi
{"title":"Correction: Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E","authors":"C. Andrieu, D. Taieb, V. Baylot, S. Ettinger, P. Soubeyran, A. De-Thonel, C. Nelson, C. Garrido, A. So, L. Fazli, F. Bladou, M. Gleave, J. L. Iovanna, P. Rocchi","doi":"10.1038/s41388-025-03531-9","DOIUrl":"10.1038/s41388-025-03531-9","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 34","pages":"3151-3151"},"PeriodicalIF":7.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03531-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799682","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}
{"title":"Retraction Note: Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway","authors":"Shaobin Huang, Wuguo Deng, Peng Wang, Yue Yan, Chuanbo Xie, Xiaoling Cao, Miao Chen, Changlin Zhang, Dingbo Shi, Yunxian Dong, Pu Cheng, Hailin Xu, Wenkai Zhu, Zhicheng Hu, Bing Tang, Jiayuan Zhu","doi":"10.1038/s41388-025-03524-8","DOIUrl":"10.1038/s41388-025-03524-8","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 34","pages":"3152-3152"},"PeriodicalIF":7.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03524-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789597","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}
OncogenePub Date : 2025-08-05DOI: 10.1038/s41388-025-03519-5
Hiroki Ozawa, Yin Wang, Henry G. Withers, Naoki Haratake, Ayako Nakashoji, Atrayee Bhattacharya, Atsushi Fushimi, Chie Kikutake, Kazuhiro Yamanoi, Shaowen White, Keyi Wang, Tatsuaki Daimon, Keisuke Shigeta, Kazumasa Fukuda, Hirofumi Kawakubo, Yuko Kitagawa, Mark D. Long, Benjamin E. Gewurz, Donald Kufe
{"title":"MUC1-C auto-regulatory complex with EBNA1 is responsible for latent Epstein-Barr virus-associated gastric cancer progression","authors":"Hiroki Ozawa, Yin Wang, Henry G. Withers, Naoki Haratake, Ayako Nakashoji, Atrayee Bhattacharya, Atsushi Fushimi, Chie Kikutake, Kazuhiro Yamanoi, Shaowen White, Keyi Wang, Tatsuaki Daimon, Keisuke Shigeta, Kazumasa Fukuda, Hirofumi Kawakubo, Yuko Kitagawa, Mark D. Long, Benjamin E. Gewurz, Donald Kufe","doi":"10.1038/s41388-025-03519-5","DOIUrl":"10.1038/s41388-025-03519-5","url":null,"abstract":"Latent Epstein-Barr Virus (EBV) infection promotes cancers derived from B-lymphocytes and epithelial cells by mechanisms that largely remain unclear. EBV-encoded nuclear antigen 1 (EBNA1) is uniformly expressed in EBV-associated cancers; however, how EBNA1 contributes to cancer progression is not known. The MUC1 gene evolved in mammals to protect barrier tissues from viral infections. We report that MUC1 is upregulated in EBV-associated gastric cancers (EBVaGCs). Our results demonstrate that EBNA1 and the oncogenic MUC1-C subunit form an auto-regulatory complex that controls expression of EBNA1, MUC1-C and host cellular genes. EBNA1 appropriates MUC1-C to (i) induce DNA methyltransferase (DNMT) expression and DNA methylation, (ii) suppress CDKN1A encoding p21 to promote proliferation, and (iii) upregulate survivin to confer survival. MUC1-C is also co-opted for localization of EBNA1 in chromatin, expression of EBV latency genes and suppression of lytic genes. Targeting MUC1-C thereby induces the switch of EBV latency to activation of the lytic phase. We further demonstrate that MUC1-C is necessary for EBVaGC stem cell (CSC) state as evidenced by regulation of NOTCH stemness genes and self-renewal capacity. These findings and the demonstration that EBV positivity has no significant effect on survival of patients with GCs indicate that EBNA1 exploits MUC1-C to maintain EBV latency and that prolonged activation of MUC1-C in response to chronic EBV infection promotes EBVaGC malignant progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3609-3624"},"PeriodicalIF":7.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03519-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789596","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}
OncogenePub Date : 2025-08-04DOI: 10.1038/s41388-025-03507-9
Zeinab Kosibaty, Cuyler Luck, Ross A. Okimoto
{"title":"The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE)","authors":"Zeinab Kosibaty, Cuyler Luck, Ross A. Okimoto","doi":"10.1038/s41388-025-03507-9","DOIUrl":"10.1038/s41388-025-03507-9","url":null,"abstract":"Transcription factor (TF) fusion oncoproteins represent cancer-specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease-driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion-mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition, leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC::DUX4 tumor growth in vitro and tumor formation in vivo. Collectively, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3598-3608"},"PeriodicalIF":7.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03507-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784916","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}
OncogenePub Date : 2025-08-04DOI: 10.1038/s41388-025-03517-7
Jing-Lan Hao, Jia-Qi He, Hang Hu, Zi-Heng Zhu, Xi Zhao, Xiao-Yu Wu, Lan Li, Yong-Tong Ruan, Juan Yang, Xin-Yi Luo, Wang-Xue Xu, Ming Fu, Kai Zhang, Ping Gao, Xiao-Ming Dong
{"title":"TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity","authors":"Jing-Lan Hao, Jia-Qi He, Hang Hu, Zi-Heng Zhu, Xi Zhao, Xiao-Yu Wu, Lan Li, Yong-Tong Ruan, Juan Yang, Xin-Yi Luo, Wang-Xue Xu, Ming Fu, Kai Zhang, Ping Gao, Xiao-Ming Dong","doi":"10.1038/s41388-025-03517-7","DOIUrl":"10.1038/s41388-025-03517-7","url":null,"abstract":"Prostate cancer is one of the malignancies affecting men and contributes significantly to their increased mortality rates. Understanding the molecular mechanisms underlying the initiation and progression of prostate cancer is important for identifying potential drug targets. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-β1 to activate TGF-β signaling pathway. Moreover, LINC01179 interacted with Miz1 to attenuate TLL1 expression and LINC01179 impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-β signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-β signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+ T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+ T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3580-3597"},"PeriodicalIF":7.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784917","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}
OncogenePub Date : 2025-08-04DOI: 10.1038/s41388-025-03523-9
Eric Vigneul, Fanny Krins, Frédéric Clotman
{"title":"Of travelling homeoproteins and medulloblastomas","authors":"Eric Vigneul, Fanny Krins, Frédéric Clotman","doi":"10.1038/s41388-025-03523-9","DOIUrl":"10.1038/s41388-025-03523-9","url":null,"abstract":"Medulloblastomas are the most common solid paediatric cancers. Their prognosis largely depends on tumour subtype and expression level of transcription factor such as Orthodenticle homeobox 2 (OTX2). OTX2 is an homeoprotein that maintains stemness and initiates oncogenic pathways. Additionally, as many other homeoproteins, OTX2 is able to travel between cells and to modify the transcriptional activity of recipient ones. After identifying travelling proteins in in vivo models, a systematic review of the literature highlighted that at least eleven travelling homeoproteins are associated with medulloblastoma: Cut like homeobox 1 (CUX1), Engrailed homeobox 1 and 2 (EN1 and EN2), Insulin gene enhancer protein ISL-1 (ISL1), LIM homeobox 1 (LHX1), Homeobox protein Nkx-2.2 (NKX2.2), OTX2, Paired box protein Pax-5,6 and 8 (PAX5, PAX6 and PAX8), as well as POU domain, class 5, transcription factor 1 (POU5F1). Overexpression of some of these homeoprotein-coding gene including OTX2 and POU5F1 was found to be associated with poor prognosis, while overexpression of PAX8 seems to have a protective effect, with a significantly better overall and progression-free survival. Research efforts to better understand the transfer mechanisms and intracellular targets of these transcription factors may offer a new range of therapeutics tools, by interfering with these roaming oncoproteins to circumscribe their associated chain reaction of genetic deregulation, or by providing protective homeoprotein supplementation with the aim of stemming tumour development by direct cancer cell penetration and reprograming.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 34","pages":"3043-3051"},"PeriodicalIF":7.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784915","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}
OncogenePub Date : 2025-08-02DOI: 10.1038/s41388-025-03511-z
Pablo Sanchis, Agustina Sabater, Julia Lechuga, Jimena Rada, Rocio Seniuk, Gaston Pascual, Mora Gatti, Juan Bizzotto, Peter D. A. Shepherd, Jun Yang, Javier Cotignola, Elba Vazquez, Joaquin Mateo, Pia Valacco, Estefania Labanca, Christopher Logothetis, Geraldine Gueron, Nicolas Anselmino
{"title":"PKA-driven SPP1 activation as a novel mechanism connecting the bone microenvironment to prostate cancer progression","authors":"Pablo Sanchis, Agustina Sabater, Julia Lechuga, Jimena Rada, Rocio Seniuk, Gaston Pascual, Mora Gatti, Juan Bizzotto, Peter D. A. Shepherd, Jun Yang, Javier Cotignola, Elba Vazquez, Joaquin Mateo, Pia Valacco, Estefania Labanca, Christopher Logothetis, Geraldine Gueron, Nicolas Anselmino","doi":"10.1038/s41388-025-03511-z","DOIUrl":"10.1038/s41388-025-03511-z","url":null,"abstract":"Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or C42B/MC3T3 cell lines), and in vivo, using cell lines’ engraftments and patient-derived xenografts (PDX) grown intrafemorally. Importantly, clinical data from longitudinal patient samples revealed that treatment with enzalutamide, an androgen receptor (AR) inhibitor, led to an increase in PKA signaling and corresponding SPP1 expression in a subpopulation of patients, highlighting the relevance of the PKA/SPP1 axis in disease progression under AR-targeted therapies. Overall, we underscored the critical role of the bone microenvironment in influencing PCa progression, pointing out to SPP1/OPN as a biomarker for identifying tumors with active PKA signaling, which could serve to manage resistance to AR-directed treatments.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3568-3579"},"PeriodicalIF":7.3,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03511-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768839","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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