OncogenePub Date : 2025-07-28DOI: 10.1038/s41388-025-03513-x
Zou Li, Rui Liu, Zhihong Fang, Rui Chen, Daoyan Yang, Yuan Li, Shurong Liu, Chong Wang, Huan Liu
{"title":"LAMP5 modulates IRF4 stability and nuclear transport: a critical mechanism in myeloma progression and therapy","authors":"Zou Li, Rui Liu, Zhihong Fang, Rui Chen, Daoyan Yang, Yuan Li, Shurong Liu, Chong Wang, Huan Liu","doi":"10.1038/s41388-025-03513-x","DOIUrl":"10.1038/s41388-025-03513-x","url":null,"abstract":"Multiple myeloma is a malignant hematopoietic neoplasm characterized by unclear molecular mechanisms and lack of highly effective targeted therapies for clinical application. Interferon regulatory factor 4 (IRF4) is a well-known core transcription factor that regulates the progression of myeloma, but the molecular mechanisms underlying its protein homeostasis regulation are unknown. Our research shows that lysosomal-associated membrane protein 5 (LAMP5) interacts with IRF4 and prevents its degradation through the autophagy-lysosome pathway, thereby facilitating the progression of myeloma. Additionally, LAMP5 enhances the interaction between IRF4 and the nuclear transport protein karyopherin α2 (KPNA2), facilitating the nuclear transport of IRF4 and preventing its cytoplasmic retention and subsequent autophagy-lysosome degradation. Nuclear IRF4 promotes the transcription of c-MYC, and the c-MYC protein positively feeds back to activate LAMP5 transcription. This vicious regulatory loop drives rapid progression of myeloma. High-throughput drug screening shows pyrazofurin that significantly disrupts the interaction between LAMP5 and IRF4, leading to the degradation of IRF4 and inhibition of myeloma progression. This study elucidates a novel mechanism underlying IRF4 protein homeostasis maintenance and provides a potential inhibitor for myeloma treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3553-3567"},"PeriodicalIF":7.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03513-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732500","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 : 2025-07-28DOI: 10.1038/s41388-025-03496-9
Joaquin Olmedo-Pelayo, Esperanza Granado-Calle, Daniel Delgado-Bellido, Laura Lobo-Selma, Carmen Jordan-Perez, Ana T. Monteiro-Amaral, Anna C. Ehlers, Shunya Ohmura, Daniel J. Garcia-Dominguez, Carlos Mackintosh, Angel M. Carcaboso, Javier Alonso, Isidro Machado, Antonio Llombart-Bosch, Katia Scotlandi, Thomas G. P. Grünewald, Fernando Gomez-Herreros, Enrique de Alava
{"title":"EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism","authors":"Joaquin Olmedo-Pelayo, Esperanza Granado-Calle, Daniel Delgado-Bellido, Laura Lobo-Selma, Carmen Jordan-Perez, Ana T. Monteiro-Amaral, Anna C. Ehlers, Shunya Ohmura, Daniel J. Garcia-Dominguez, Carlos Mackintosh, Angel M. Carcaboso, Javier Alonso, Isidro Machado, Antonio Llombart-Bosch, Katia Scotlandi, Thomas G. P. Grünewald, Fernando Gomez-Herreros, Enrique de Alava","doi":"10.1038/s41388-025-03496-9","DOIUrl":"10.1038/s41388-025-03496-9","url":null,"abstract":"Drug resistance is an ill-defined cause of dismal outcomes in cancer. Ewing sarcoma (EwS), a pediatric cancer characterized by high therapy failure rates, is driven by a single oncogenic event generating EWSR1::ETS gene fusions (primarily EWSR1::FLI1) in a silent genomic background. This provides a straightforward model to study the impact of gene fusions on drug responses. Here, we describe a novel mechanism of sensitivity to DNA topoisomerase 1 poisons in EwS. We discovered that EWS::FLI1 prevents the resolution of R-loops induced by these drugs via sequestering DHX9 helicase, ultimately resulting in R-loop accumulation, replication stress, and genome instability. In turn, excessive DHX9 or reduced EWS::FLI1 levels render EwS cells resistant to the active metabolite of irinotecan (SN-38) independent of proliferation and global transcription rates. This resistance helps explain how elevated DHX9 levels predict worse clinical outcomes. Overall, our research demonstrates the impact of a dominant mutation on cancer drug sensitivity, highlighting its significant clinical implications.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 38","pages":"3537-3552"},"PeriodicalIF":7.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03496-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732499","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 : 2025-07-28DOI: 10.1038/s41388-025-03509-7
G. Mantovani, S. Bondioni, A. G. Lania, M. Rodolfo, E. Peverelli, N. Polentarutti, T. Veliz Rodriguez, S. Ferrero, S. Bosari, P. Beck-Peccoz, A. Spada
{"title":"Retraction Note: High expression of PKA regulatory subunit 1A protein is related to proliferation of human melanoma cells","authors":"G. Mantovani, S. Bondioni, A. G. Lania, M. Rodolfo, E. Peverelli, N. Polentarutti, T. Veliz Rodriguez, S. Ferrero, S. Bosari, P. Beck-Peccoz, A. Spada","doi":"10.1038/s41388-025-03509-7","DOIUrl":"10.1038/s41388-025-03509-7","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 33","pages":"3040-3040"},"PeriodicalIF":7.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03509-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732502","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":"PABPN1-C5 axis promotes hepatocellular carcinoma progression via NF-κB activation","authors":"Siyao Guo, Qiang Zhang, Jieyi Ma, Yutong Zou, Zhaoyu Wang, Siyi Zheng, Hongshen Qiu, Junho Choe, Shuibin Lin, Canfeng Zhang","doi":"10.1038/s41388-025-03501-1","DOIUrl":"10.1038/s41388-025-03501-1","url":null,"abstract":"RNA polyadenylation is a key post-transcriptional modification essential for gene expression regulation. However, the role and mechanism of polyadenylation and its key molecule, polyadenylate binding protein nuclear 1 (PABPN1), in hepatocellular carcinoma (HCC) remain poorly understood. This study investigates the role of PABPN1 and its regulatory genes in HCC progression to identify potential therapeutic targets. Analysis of The Cancer Genome Atlas (TCGA) dataset and an independent HCC cohort revealed significant upregulation of PABPN1 in HCC patients, which correlates with poor prognosis. Loss-of-function studies using HCC cell lines and conditional knockout mouse models demonstrated that targeting PABPN1 inhibited HCC progression. Conversely, overexpression of PABPN1 promoted HCC development in vitro and in a hydrodynamic transfection hepatocarcinogenesis mouse model. Mechanistic investigations showed that PABPN1 modulates C5 mRNA polyadenylation and stability, with the PABPN1-C5 axis driving NF-κB activation and recruiting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to promote HCC progression. Therapeutic targeting of the PABPN1-C5 axis using the C5a receptor inhibitor CCX168 significantly inhibited HCC progression in both in vitro and in vivo models. This study identifies PABPN1 as a critical regulator of HCC development and sheds light on the post-transcriptional regulation of complement components in cancer. Targeting the PABPN1-C5 axis represents a promising strategy for HCC treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 37","pages":"3512-3524"},"PeriodicalIF":7.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732501","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 : 2025-07-26DOI: 10.1038/s41388-025-03492-z
Lifeng Tian, Xuanmao Jiao, Chenguang Wang, Danni Li, Adam Ertel, Joanna Achinger-Kawecka, Sankar Addya, Raymond E. Soccio, Eric R. Chen, Balázs Győrffy, Gabriele Di Sante, Zhijiu Zhong, Haidar Alkhafaji, Nina Entcheva, Elyssa M. Campbell, Peter A. McCue, Andrew V. Kossenkov, Rita Pancsa, Peter Tompa, Susan J. Clark, Richard G. Pestell
{"title":"PPARγ acetylation governs mammary adenocarcinoma tumor growth via acetylated residues that determine DNA sequence-specific binding","authors":"Lifeng Tian, Xuanmao Jiao, Chenguang Wang, Danni Li, Adam Ertel, Joanna Achinger-Kawecka, Sankar Addya, Raymond E. Soccio, Eric R. Chen, Balázs Győrffy, Gabriele Di Sante, Zhijiu Zhong, Haidar Alkhafaji, Nina Entcheva, Elyssa M. Campbell, Peter A. McCue, Andrew V. Kossenkov, Rita Pancsa, Peter Tompa, Susan J. Clark, Richard G. Pestell","doi":"10.1038/s41388-025-03492-z","DOIUrl":"10.1038/s41388-025-03492-z","url":null,"abstract":"Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Defining the molecular mechanisms governing the selection of canonical versus non-canonical PPARγ binding sequences may provide the opportunity to design regulators with distinct functions and side effects. Acetylation at K268/293 in mouse Pparγ2 participates in the regulation of adipose tissue differentiation, and the conserved lysine residues (K154/155) in mouse Pparγ1 governs lipogenesis in breast cancer cells. Herein, the PPARγ1 acetylated residues K154/155 were shown to be essential for oncogenic ErbB2 driven breast cancer growth and mammary tumor stem cell expansion in vivo. The induction of transcriptional modules governing growth factor signaling, lipogenesis, cellular apoptosis, and stem cell expansion were dependent upon K154/155. The acetylation status of the K154/155 residues determined the selection of genome-wide DNA binding sites, altering the selection from canonical to non-canonical (C/EBP) DNA sequence-specific binding. The gene signature reflecting the acetylation-dependent genomic occupancy in lipogenesis provided predictive value in survival outcomes of ErbB2+ breast cancer. The Pparγ1 acetylation site is critical for ErbB2-induced breast cancer tumor growth and may represent a relevant target for therapeutic coextinction.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 37","pages":"3476-3492"},"PeriodicalIF":7.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03492-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718243","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 : 2025-07-26DOI: 10.1038/s41388-025-03499-6
Liantao Guo, Yan Rao, Yawen Song, Jiawei Hu, Zixuan Luo, Shengrong Sun, Chuang Chen, Deguang Kong
{"title":"SIX1 transmits signals for breast cancer progression via the ZEB1/IL6/STAT3 signaling axis","authors":"Liantao Guo, Yan Rao, Yawen Song, Jiawei Hu, Zixuan Luo, Shengrong Sun, Chuang Chen, Deguang Kong","doi":"10.1038/s41388-025-03499-6","DOIUrl":"10.1038/s41388-025-03499-6","url":null,"abstract":"Epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSCs) are pivotal in breast cancer mechanism research. It was demonstrated that Sine oculis homeobox homolog 1 (SIX1) orchestrates breast cancer EMT and BCSCs, concurrently activating the Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Yet, the mechanism by which SIX1 modulates STAT3 and its potential to regulate EMT and BCSCs through STAT3 signaling remain unexplored. Here, cellular, animal, organoid models, and integrated single-cell transcriptomic and ST-seq of human breast cancer specimens were conducted. The results revealed that SIX1 can enhance Zinc finger E-box binding homeobox 1 (ZEB1) expression and translation, which in turn binds to the Interleukin-6 (IL6) promoter (1138bp–1148bp) to stimulate its transcription, translation, and secretion. Subsequently, IL6 can activate the cell’s own STAT3 signaling pathway, promote the phosphorylation of STAT3, promote the downstream signal c-Myc and Cyclin D1 transduction, and promote the expression of stem cell-related transcription factors such as ALDH1A1, OCT4, and SOX2, thereby promoting EMT and stemness. In addition, this study found a new cell interaction model, in which the above-mentioned secreted IL6 can promote the activation of STAT3 signaling pathway, EMT and stemness transformation in the surrounding cells with low expression of SIX1 in a paracrine manner. Our data favored that SIX1/ZEB1/IL6 axis activated the STAT3 signaling pathway of the breast cells themselves and surrounding cells with low SIX1 expression, thus promoting EMT and stemness transformation, activating the malignant progression of the whole breast cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 37","pages":"3493-3511"},"PeriodicalIF":7.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03499-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718245","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":"RFX2-BNIP3 axis-driven adaptive mitophagy promotes resistance to ACK1-targeted therapy in non-small cell lung cancer","authors":"Kui Cao, Shenshui Wei, Tianjiao Ma, Xiaolong Zou, Hongxue Meng, Xinxin Yang, Mengdi Lu, Yuning Wang, Xiangrong He, Jianqun Ma, Jinhong Zhu","doi":"10.1038/s41388-025-03502-0","DOIUrl":"10.1038/s41388-025-03502-0","url":null,"abstract":"Activated Cdc42-associated kinase 1 (ACK1) is an oncogenic non-receptor kinase that promotes tumor cell survival and impairs T-cell activation. Targeting ACK1 has great promise in cancer control. However, tumor adaptive responses that may limit the anticancer efficacy of ACK1 inhibition (ACK1i) remain unclear. We found that ACK1i treatment triggered the PINK1/PARKIN-mediated adaptive mitophagy by upregulating the mitophagy receptor BNIP3. Mass/Spectrometry and co-immunoprecipitation (Co-IP) results indicated that ACK1 interacted with transcription factor regulatory factor X 2 (RFX2) through its MHR domain, and competitively inhibits RFX2 ubiquitination via the E3 ubiquitin ligase MIB1. Conversely, ACK1i facilitates MIB1-mediated RFX2 ubiquitination and degradation. Moreover, we observed that RFX2 is a transcriptional suppressor of BNIP3 using luciferase reporter gene assays and chromatin immunoprecipitation (ChIP). Overall, ACK1i treatment causes RFX2 instability and thereby diminishes RFX2’s suppressive effects on BNIP3 transcription, leading to BNIP3 accumulation and the activation of mitophagy pathways. This adaptive mitophagy allows NSCLC cells to survive under ACK1 inhibition, potentially reducing the efficacy of ACK1i. ACK1i combined with mitophagy-inhibiting agents may attain a more accomplished response in NSCLC. In conclusion, ACK1i induced mitophagy through the release of RFX2 inhibition on BNIP3 transcription, thereby driving adaptive resistance. Inhibiting mitophagy sensitizes NSCLC to ACK1i.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 37","pages":"3461-3475"},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718244","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}
{"title":"Liquid-liquid phase separation of GPS2-LATS1 promotes colorectal cancer progression by reprogramming lipid metabolism","authors":"Yuliang Ren, Junjie Chen, Xiangrong Zhan, Songran Sheng, Yifan Zhong, Manxiang Gu, Xuewen Liu, Liang Zhang, Lei Bao, Yuan Si, Ying Liu","doi":"10.1038/s41388-025-03498-7","DOIUrl":"10.1038/s41388-025-03498-7","url":null,"abstract":"Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC), yet the underlying regulatory mechanisms remain incompletely understood. Here, we identified G protein pathway suppressor 2 (GPS2) as a pivotal oncogenic driver that orchestrates lipid metabolic reprogramming to fuel CRC progression. Clinically, GPS2 is overexpressed in CRC and is correlated with aggressive phenotypes. Functionally, GPS2 depletion inhibits tumor growth in vitro and in vivo, whereas its overexpression accelerates malignancy. Mechanistically, GPS2 dual-regulates lipid metabolism by facilitating the nuclear translocation of sterol regulatory element-binding protein 1 (SREBP1) to activate lipid synthesis and by increasing peroxisome proliferator-activated receptor α (PPARα) transcription to promote fatty acid oxidation. Crucially, we revealed that GPS2 undergoes liquid-liquid phase separation (LLPS) in CRC cells, where it forms biomolecular condensates that promote oncogenic signaling. Through its coiled-coil domain, phase-separated GPS2 directly interacts with the C-terminal kinase domain of large tumor suppressor 1 (LATS1), a core kinase of the Hippo pathway, inducing LLPS of LATS1 and suppressing its activity. This inactivation releases YAP, which in turn amplifies SREBP1/PPARα-driven lipid metabolism. Rescue experiments confirmed that YAP reconstitution restores SREBP1 nuclear translocation and PPARα transcription upon GPS2 loss, establishing the LATS1-YAP axis as the central effector of GPS2-mediated lipid metabolic programming. Our study delineates a novel phase separation-dependent mechanism whereby GPS2 spatially reorganizes LATS1-YAP signaling to reprogram lipid metabolism and promote CRC progression, suggesting potential therapeutic targets for metabolic intervention in CRC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 39","pages":"3741-3754"},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718242","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}
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