Oncogene最新文献

{"title":"AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer","authors":"Sumaira Sardar, Christopher M. McNair, Lakshmi Ravindranath, Saswati N. Chand, Wei Yuan, Denisa Bogdan, Jon Welti, Adam Sharp, Natalie K. Ryan, Liam A. Knudsen, Matthew J. Schiewer, Elise G. DeArment, Thomas Janas, Xiaofeng A. Su, Lisa M. Butler, Johann S. de Bono, Kris Frese, Nigel Brooks, Neil Pegg, Karen E. Knudsen, Ayesha A. Shafi","doi":"10.1038/s41388-024-03148-4","DOIUrl":"https://doi.org/10.1038/s41388-024-03148-4","url":null,"abstract":"<p>Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factors in vitro, in vivo, and in human prostate cancer (PCa) tumors ex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207393","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":"Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis","authors":"Clarissa N. Pacyna, Madhanagopal Anandapadamanaban, Kevin W. Loudon, Iain M. Hay, Olga Perisic, Ruoyan Li, Matthew Byrne, Laura Allen, Kirsty Roberts, Yvette Hooks, Anne Y. Warren, Grant D. Stewart, Menna R. Clatworthy, Sarah A. Teichmann, Sam Behjati, Peter J. Campbell, Roger L. Williams, Thomas J. Mitchell","doi":"10.1038/s41388-024-03137-7","DOIUrl":"https://doi.org/10.1038/s41388-024-03137-7","url":null,"abstract":"<p>Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared <i>MTOR</i> mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207355","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":"ZG16 enhances the maturation of dendritic cells via induction of CD40 and contributes to the antitumor immunity in pancreatic cancer","authors":"Hui Meng, Ling Li, Manman Nan, Yi Ding, Yizhen Li, Mingzhi Zhang","doi":"10.1038/s41388-024-03154-6","DOIUrl":"https://doi.org/10.1038/s41388-024-03154-6","url":null,"abstract":"<p>Dendritic cells (DCs) are critical mediators of antigen priming and T-cell activation. Zymogen granule protein 16 (ZG16) is demonstrated as an anti-oncogene in T-cell mediated antitumor immunity, but its effect on DCs is largely unknown. Herein, we wonder whether ZG16 affects the activation of DCs in pancreatic cancer. Firstly, the increased ZG16 expression was observed during the maturation of DCs derived from mouse bone marrow or human peripheral blood. Then, overexpression of ZG16 or exogenous introduction of recombinant ZG16 protein induced the expression of MHC II, CD86, CD84, and CCR7 on the surface of DCs, thereby facilitating the secretion of proinflammatory mediators IL-1β, IL-6, TNF-α, and IL-12/p70, supporting the promoting effect of ZG16 on DC maturation. By establishing the subcutaneous and orthotopic mouse models of pancreatic cancer, we confirmed that intraperitoneal injection of recombinant ZG16 protein (Re-mZG16) could induce tumor regression by stimulating DC maturation and enhancing antitumor responses of CD4 + , CD8 + , PD-1 + , and Ctla4+ cells. Besides, Re-mZG16 in combination with gemcitabine showed a synergistic effect in the treatment of pancreatic cancer. Mechanistically, we demonstrated that ZG16 inhibited the ubiquitination and degradation of CD40, which depended on the lectin domain of ZG16. In conclusion, this study provided a novel insight into the role of ZG16-CD40 axis in DC-based immunotherapy for pancreatic cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207397","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":"USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2","authors":"Jiming Chen, Wulin Shan, Qiucheng Jia, Yao Chen, Wenjing Jiang, Yuan Tian, Xu Huang, Xiaoyu Li, Zengying Wang, Bairong Xia","doi":"10.1038/s41388-024-03151-9","DOIUrl":"https://doi.org/10.1038/s41388-024-03151-9","url":null,"abstract":"<p>Post-translational modifications of proteins play a pivotal role in both the initiation and progression of ovarian cancer. Despite the recognition of USP33 as a significant factor in various cancers, its specific function and underlying mechanisms in ovarian cancer remain elusive. Proteomics and ubiquitinomics approaches were coupled to screen novel substrate proteins directly regulated by USP33. Our findings unveil that USP33 was observed to eliminate K27- and K48-linked ubiquitin chains from CBX2 at the K277 position. Notably, acetylation of CBX2 at K199, catalyzed by lysine acetyltransferase GCN5, was found to enhance its interaction with USP33, subsequently promoting further deubiquitination and stabilization. Functionally, our experiments demonstrate that USP33 significantly enhances ovarian cancer proliferation and metastasis in a CBX2-dependent manner. Furthermore, analysis revealed a direct positive correlation between the expression levels of USP33 and CBX2 proteins in human specimens, with elevated levels being associated with reduced survival rates in ovarian cancer patients. These findings elucidate the mechanism by which USP33 augments ovarian cancer progression through the stabilization of CBX2, underscoring the USP33-CBX2 axis as a promising therapeutic target in ovarian cancer management.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207394","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":"Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression","authors":"Xinrong Li, Zhixiang Hu, Qili Shi, Wenying Qiu, Yizhe Liu, Yanfang Liu, Shenglin Huang, Linhui Liang, Zhiao Chen, Xianghuo He","doi":"10.1038/s41388-024-03150-w","DOIUrl":"https://doi.org/10.1038/s41388-024-03150-w","url":null,"abstract":"<p>An increase in the total choline-containing compound content is a common characteristic of cancer cells, and aberrant choline metabolism in cancer is closely associated with malignant progression. However, the potential role of choline-induced global transcriptional changes in cancer cells remains unclear. In this study, we reveal that an elevated choline content facilitates hepatocellular carcinoma (HCC) cell proliferation by reprogramming Krüppel-like factor 5 (KLF5)-dominated core transcriptional regulatory circuitry (CRC). Mechanistically, choline administration leads to elevated S-adenosylmethionine (SAM) levels, inducing the formation of H3K4me1 within the super-enhancer (SE) region of KLF5 and activating its transcription. KLF5, as a key transcription factor (TF) of CRC established by choline, further transactivates downstream genes to facilitate HCC cell cycle progression. Additionally, KLF5 can increase the expression of choline kinase-α (CHKA) and CTP:phosphocholine cytidylyltransferase (CCT) resulting in a positive feedback loop to promote HCC cell proliferation. Notably, the histone deacetylase inhibitor (HDACi) vorinostat (SAHA) significantly suppressed KLF5 expression and liver tumor growth in mice, leading to a prolonged lifespan. In conclusion, these findings highlight the epigenetic regulatory mechanism of the SE-driven key regulatory factor KLF5 conducted by choline metabolism in HCC and suggest a potential therapeutic strategy for HCC patients with high choline content.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207396","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":"GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma","authors":"Peiyi Xie, Mengyuan Wu, Hui Wang, Bo Zhang, Zihao Zhang, Jiuliang Yan, Mincheng Yu, Qiang Yu, Yufei Zhao, Da Huang, Min Xu, Wenxin Xu, Hui Li, Yongfeng Xu, Yongsheng Xiao, Lei Guo","doi":"10.1038/s41388-024-03153-7","DOIUrl":"https://doi.org/10.1038/s41388-024-03153-7","url":null,"abstract":"<p>Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.</p><figure></figure>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142207395","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":"ALDH1A3 is the switch that determines the balance of ALDH+ and CD24−CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer","authors":"Wasundara Fernando, Brianne M. Cruickshank, Raj Pranap Arun, Maya R. MacLean, Hannah F. Cahill, Fiorella Morales-Quintanilla, Cheryl A. Dean, Marie-Claire D. Wasson, Margaret L. Dahn, Krysta M. Coyle, Olivia L. Walker, Melanie R. Power Coombs, Paola Marcato","doi":"10.1038/s41388-024-03156-4","DOIUrl":"https://doi.org/10.1038/s41388-024-03156-4","url":null,"abstract":"<p>Plasticity is an inherent feature of cancer stem cells (CSCs) and regulates the balance of key processes required at different stages of breast cancer progression, including epithelial-to-mesenchymal transition (EMT) versus mesenchymal-to-epithelial transition (MET), and glycolysis versus oxidative phosphorylation. Understanding the key factors that regulate the switch between these processes could lead to novel therapeutic strategies that limit tumor progression. We found that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates these cancer-promoting processes and the abundance of the two distinct breast CSC populations defined by high ALDH activity and CD24⁻CD44⁺ cell surface expression. While ALDH1A3 increases ALDH⁺ breast cancer cells, it inversely suppresses the CD24⁻CD44⁺ population by retinoic acid signaling-mediated gene expression changes. This switch in CSC populations induced by ALDH1A3 was paired with decreased migration but increased invasion and an intermediate EMT phenotype. We also demonstrate that ALDH1A3 increases oxidative phosphorylation and decreases glycolysis and reactive oxygen species (ROS). The effects of ALDH1A3 reduction were countered with the glycolysis inhibitor 2-deoxy-D-glucose (2DG). In cell culture and tumor xenograft models, 2DG suppresses the increase in the CD24⁻CD44⁺ population and ROS induced by ALDH1A3 knockdown. Combined inhibition of ALDH1A3 and glycolysis best reduces breast tumor growth and tumor-initiating cells, suggesting that the combination of targeting ALDH1A3 and glycolysis has therapeutic potential for limiting CSCs and tumor progression. Together, these findings identify ALDH1A3 as a key regulator of processes required for breast cancer progression and depletion of ALDH1A3 makes breast cancer cells more susceptible to glycolysis inhibition.</p><figure></figure>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226590","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":"Loss of DOCK2 potentiates Inflammatory Bowel Disease-associated colorectal cancer via immune dysfunction and IFNγ induction of IDO1 expression.","authors":"Antonia M D Churchhouse, Caroline V Billard, Toshiyasu Suzuki, Sebastian Ö G Pohl, Nora J Doleschall, Kevin Donnelly, Colin Nixon, Mark J Arends, Shahida Din, Kathryn Kirkwood, Jair Marques Junior, Alex Von Kriegsheim, Seth B Coffelt, Kevin B Myant","doi":"10.1038/s41388-024-03135-9","DOIUrl":"https://doi.org/10.1038/s41388-024-03135-9","url":null,"abstract":"<p><p>Inflammatory Bowel Disease-associated colorectal cancer (IBD-CRC) is a known and serious complication of Inflammatory Bowel Disease (IBD) affecting the colon. However, relatively little is known about the pathogenesis of IBD-associated colorectal cancer in comparison with its sporadic cancer counterpart. Here, we investigated the function of Dock2, a gene mutated in ~10% of IBD-associated colorectal cancers that encodes a guanine nucleotide exchange factor (GEF). Using a genetically engineered mouse model of IBD-CRC, we found that whole body loss of Dock2 increases tumourigenesis via immune dysregulation. Dock2-deficient tumours displayed increased levels of IFNγ-associated genes, including the tryptophan metabolising, immune modulatory enzyme, IDO1, when compared to Dock2-proficient tumours. This phenotype was driven by increased IFNγ-production in T cell populations, which infiltrated Dock2-deficient tumours, promoting IDO1 expression in tumour epithelial cells. We show that IDO1 inhibition delays tumourigenesis in Dock2 knockout mice, and we confirm that this pathway is conserved across species as IDO1 expression is elevated in human IBD-CRC and in sporadic CRC cases with mutated DOCK2. Together, these data demonstrate a previously unidentified tumour suppressive role of DOCK2 that limits IFNγ-induced IDO1 expression and cancer progression, opening potential new avenues for therapeutic intervention.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146093","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":"Editorial Expression of Concern: Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer.","authors":"Simone Fulda, Martin U Kuüfer, Eric Meyer, Frans van Valen, Barbara Dockhorn-Dworniczak, Klaus-Michael Debatin","doi":"10.1038/s41388-024-03158-2","DOIUrl":"https://doi.org/10.1038/s41388-024-03158-2","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146092","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":"Editorial Expression of Concern: RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells.","authors":"Dharminder Chauhan, Teru Hideshima, Pramod Pandey, Steve Treon, Gerrard Teoh, Noopur Raje, Steven Rosen, Nancy Krett, Hervé Husson, Shalom Avraham, Surender Kharbanda, Kenneth C Anderson","doi":"10.1038/s41388-024-03152-8","DOIUrl":"https://doi.org/10.1038/s41388-024-03152-8","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140699","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}