Oncogene最新文献_第2页

Integration of germline pharmacogenomic burden to predict fluoropyrimidine-related toxicity - A secondary analysis of the PREPARE trial. 结合种系药物基因组负担预测氟嘧啶相关毒性——PREPARE试验的二次分析

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-25 DOI: 10.1038/s41388-025-03587-7

Elena De Mattia, Yoomi Park, Elena Peruzzi, Yitian Zhou, Rossana Roncato, Jerry Polesel, Lucia Scarabel, Matthias Schwab, Henk-Jan Guchelaar, Jesse Joachim Swen, Michele Spina, Fabio Puglisi, Giuseppe Toffoli, Volker M Lauschke, Erika Cecchin

{"title":"Integration of germline pharmacogenomic burden to predict fluoropyrimidine-related toxicity - A secondary analysis of the PREPARE trial.","authors":"Elena De Mattia, Yoomi Park, Elena Peruzzi, Yitian Zhou, Rossana Roncato, Jerry Polesel, Lucia Scarabel, Matthias Schwab, Henk-Jan Guchelaar, Jesse Joachim Swen, Michele Spina, Fabio Puglisi, Giuseppe Toffoli, Volker M Lauschke, Erika Cecchin","doi":"10.1038/s41388-025-03587-7","DOIUrl":"https://doi.org/10.1038/s41388-025-03587-7","url":null,"abstract":"Testing for four dihydropyrimidine dehydrogenase (DPYD) variants (DPYD*2 A, DPYD*13, c.2846 A > T, DPYD-HapB3) is currently implemented in clinical practice to prevent fluoropyrimidines (FLs) related toxicity but with limited sensitivity. This study aimed to identify novel genetic factors in FL-related genes to enhance risk prediction using data from the PREPARE trial (NCT03093818). Two hundred seventy-four patients receiving FL-based chemotherapy with severe toxicity were sequenced for 60 candidate genes. Gene and pathway-level association analyses focusing mainly on rare variants were performed using dedicated statistical tests, including gene-wise variant burden (GVB) analysis. DPYD germline variant burden beyond the four routinely tested markers emerged to contribute to toxicity, indicating that rarer genetic variants could help in refining the optimal FL dosage (p < 0.1). Functional rare variant burden in ABCB5, PARP1, ENOSF1, CYP3A4 and nuclear receptors pathway impacted on toxicity risk (p < 0.05 in at least one statistical test). GVB analysis confirmed ABCB5 as a significant risk gene and highlighted ABCC4, HNF4A, and XRCC3 as additional candidates. A predictive model combining genetic burden scores with clinical variables improved the identification of high-risk patients (sensitivity=0.71, specificity=0.74, accuracy=0.73). This study indicated a paradigm shift from population to individual-level arguing for an extension of testing beyond the four DPYD currently considered variants to predict FL-related toxicity.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150369","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}

引用次数: 0

RAD51-mediated homologous recombination is a pro-tumour driver pathway rad51介导的同源重组是促肿瘤驱动通路。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-24 DOI: 10.1038/s41388-025-03583-x

Bernard S. Lopez

{"title":"RAD51-mediated homologous recombination is a pro-tumour driver pathway","authors":"Bernard S. Lopez","doi":"10.1038/s41388-025-03583-x","DOIUrl":"10.1038/s41388-025-03583-x","url":null,"abstract":"Genetic instability is a hallmark of cancer cells. Homologous recombination (HR) plays a pivotal role in maintaining genome stability through its DNA repair and replication fork escort functions. Therefore, HR is classified as a tumour suppressor pathway. Consistently, many HR genes are mutated in cancer, especially in hereditary breast and ovarian cancer. However, although RAD51 controls the central steps of HR, no RAD51 mutations are associated with cancer predisposition, constituting the “RAD51 paradox”. One of the potential explanations for the “RAD51 paradox” is that mutations affecting mediator/accessory genes (such as BRCA1 or BRCA2) in cancer result in the absence of RAD51 on damaged DNA, leaving access to alternative exclusively mutagenic repair processes, such as single-strand annealing (SSA) or alternative end-joining (A-EJ), which can rescue some cell viability but also increase genetic instability. This raises the question of whether cancer predisposition actually results from HR deficiency itself or from alternative, nonconservative repair pathways. One study assessing this question in a mouse model revealed that decreasing RAD51 HR activity without stimulating SSA or A-EJ in vivo not only does not favour tumorigenesis but rather protects against it. These data suggest that RAD51-controlled HR is not a tumour suppressor but rather favours tumour progression. Cancer cells are highly proliferative, actively replicating their genomes, and are therefore subjected to high replication stress; pathways enabling them to cope with this massive replication stress, such as HR, should help them survive and proliferate, contrary to the belief dogma that HR acts as a tumour suppressor pathway. We propose that HR/RAD51, through its essential role in overcoming replication stress, should facilitate cancer progression as soon as early pretumorigenic hyperplasia states that trigger an active replication program, challenging commonly accepted views.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 42","pages":"4006-4016"},"PeriodicalIF":7.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03583-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138121","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}

引用次数: 0

KBTBD11 loss promotes AKT hyperactivation and therapeutic vulnerability in prostate cancer. KBTBD11缺失促进前列腺癌中AKT的过度激活和治疗易感性。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-23 DOI: 10.1038/s41388-025-03576-w

Haoyue Sheng, Guohai Shi, Yawen Lu, Shengfeng Zheng, Weijie Gu, Dan Xia, Haojie Huang, Dingwei Ye

{"title":"KBTBD11 loss promotes AKT hyperactivation and therapeutic vulnerability in prostate cancer.","authors":"Haoyue Sheng, Guohai Shi, Yawen Lu, Shengfeng Zheng, Weijie Gu, Dan Xia, Haojie Huang, Dingwei Ye","doi":"10.1038/s41388-025-03576-w","DOIUrl":"https://doi.org/10.1038/s41388-025-03576-w","url":null,"abstract":"PI3K-AKT signaling axis is often aberrantly activated in human cancers including prostate cancer, but the underlying mechanism of deregulation and tactics for effective targeting of this cancer relevant pathway remain poorly understood. Here, we demonstrate that KBTBD11 E3 ubiquitin ligase gene is frequently deleted in human prostate cancers and that KBTBD11 loss augments AKT phosphorylation in prostate cancer cells in culture and in patient samples. We show that KBTBD11 promotes lysine-27-chain polyubiquitination at lysine 8 and 14 on AKT and antagonizes ubiquitin K63 linkage-mediated polyubiquitination and phosphorylation of AKT. KBTBD11 deficiency drove prostate cancer cell growth in vitro and in vivo, but constituted as a therapeutic vulnerability to the selective AKT inhibitor in prostate cancer. Our study identifies lysine-27-chain polyubiquitination as an inhibitory mechanism of AKT activation and nominates KBTBD11 as an intrinsic upstream inhibitor of AKT. Our findings suggest that KBTBD11 deletion could be a biomarker to guide the use of the AKT inhibitors for the effective treatment of cancers such as prostate cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125064","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}

引用次数: 0

FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma. FPR3维持肿瘤相关巨噬细胞的免疫抑制，加速胃腺癌的进展。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-23 DOI: 10.1038/s41388-025-03578-8

Minqiong Sun, Zhenya Tan, Keqiong Lin, Zhiling Chang, Zhi Yang, Xue Yang, Gu Tang, Yakun Liu, Chun Li, Jicheng Zhu, Chen Kan, Chunwei Peng, Hong Zheng

{"title":"FPR3 sustains the immunosuppression of tumor-associated macrophages and accelerates the progression of gastric adenocarcinoma.","authors":"Minqiong Sun, Zhenya Tan, Keqiong Lin, Zhiling Chang, Zhi Yang, Xue Yang, Gu Tang, Yakun Liu, Chun Li, Jicheng Zhu, Chen Kan, Chunwei Peng, Hong Zheng","doi":"10.1038/s41388-025-03578-8","DOIUrl":"https://doi.org/10.1038/s41388-025-03578-8","url":null,"abstract":"Tumor-associated macrophages (TAMs) play a critical role in promoting tumor progression and represent a promising target for immunotherapeutic intervention. However, the phenotypic characteristics and polarization dynamics of TAMs remain poorly understood, largely due to the complex cellular heterogeneity within the tumor microenvironment. In this study, we comprehensively characterize the heterogeneity of TAMs in gastric adenocarcinoma (GA), with a particular focus on immunosuppressive subsets. Our findings demonstrate that TAMs undergo multidirectional differentiation and exhibit diverse immunoregulatory functions. Among them, FPR3⁺ macrophages are identified as a distinct immunosuppressive population associated with poor patient prognosis. Functional assays using shRNA-mediated knockdown and specific agonists reveal that FPR3 regulates macrophage proliferation and polarization and is essential for TAM formation and maintenance. Mechanistically, FPR3 upregulates FZD7 and CCDC88C, leading to activation of the intracellular Wnt/PCP pathway and downstream JNK signaling, thereby promoting TAM development. Collectively, our study identifies FPR3 as a novel marker of immunosuppressive TAMs, elucidates its mechanistic role in macrophage plasticity, and offers new insights into potential therapeutic strategies for targeting the tumor microenvironment in GA.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131609","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}

引用次数: 0

Adaptive cancer therapy: can non-genetic factors become its achilles heel? 适应性癌症治疗：非遗传因素会成为它的致命弱点吗？

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-22 DOI: 10.1038/s41388-025-03582-y

Gábor Valcz, Robert A. Gatenby, Beáta Újvári, Edit I. Buzás, Béla Molnár

{"title":"Adaptive cancer therapy: can non-genetic factors become its achilles heel?","authors":"Gábor Valcz, Robert A. Gatenby, Beáta Újvári, Edit I. Buzás, Béla Molnár","doi":"10.1038/s41388-025-03582-y","DOIUrl":"10.1038/s41388-025-03582-y","url":null,"abstract":"The recurrence of clinically advanced cancers is an evolutionary consequence of standard-of-care chemotherapies generally administered at maximum tolerated doses to kill as many cancer cells as possible. The inevitable appearance of resistance raises the possibility of shifting treatment goals from complete tumor eradication to long-term disease control. The latter approach is employed by adaptive therapy, which aims to inhibit the evolutionary dynamics governing the spread of resistant tumor phenotypes. Adaptive therapy changes focus from the cancer cells that are responsive to therapy to those that are resistant and ultimately govern outcome. This therapeutic approach retains a pool of sensitive cancer cells to compete with the therapy-resistant ones through dynamic dose modulation and/or timing. Thus, fluctuations of treatment-sensitive cells are used to control the resistant population and prolong tumor control with existing therapy agents. Here, we explore non-genetic mechanisms of resistance, including the protective role of the tumor stroma, the epithelial-to-mesenchymal transition, the overexpression of drug efflux pumps, and the extracellular vesicle-mediated transfer of them. These mechanisms can increase the size of the resistant population at the expense of the sensitive one, reducing the ability of adaptive therapy to force tumor evolution into controllable cycles.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 42","pages":"3999-4005"},"PeriodicalIF":7.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03582-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124773","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}

引用次数: 0

Publisher Correction: NeuroD1 drives a KAT2A-FDFT1 signaling axis to promote cholesterol biosynthesis and hepatocellular carcinoma progression via histone H3K27 acetylation NeuroD1驱动KAT2A-FDFT1信号轴，通过组蛋白H3K27乙酰化促进胆固醇生物合成和肝细胞癌进展。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-22 DOI: 10.1038/s41388-025-03574-y

Zheng Wu, Wei Duan, Ying Xiong, Jingyi Liu, Xinpeng Wen, Fuqiang Zhao, Debing Xiang, Jian Wang, Vivi Kasim, Shourong Wu

引用次数: 0

Aging-associated ZNF573 methylation regulates RNF19B-PIK3CA ubiquitination to promote prostate cancer. 衰老相关的ZNF573甲基化调节RNF19B-PIK3CA泛素化促进前列腺癌。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-19 DOI: 10.1038/s41388-025-03579-7

Yuqiu Ge, Peiyu Han, Yangyang Sun, Yuyu Chen, Qianqian Shi, Li Cui, Qinbo Yuan, Gaoxiang Ma

{"title":"Aging-associated ZNF573 methylation regulates RNF19B-PIK3CA ubiquitination to promote prostate cancer.","authors":"Yuqiu Ge, Peiyu Han, Yangyang Sun, Yuyu Chen, Qianqian Shi, Li Cui, Qinbo Yuan, Gaoxiang Ma","doi":"10.1038/s41388-025-03579-7","DOIUrl":"https://doi.org/10.1038/s41388-025-03579-7","url":null,"abstract":"Aging significantly influences the pathogenesis of prostate cancer (PCa). Emerging evidence suggests that aging-related methylation changes play a critical role in PCa. However, the impact of aging-related DNA methylation in PCa remains largely unexplored. To identify hypermethylated sites associated with aging in PCa, we performed an epigenome-wide analysis using Illumina Human Methylation BeadChip arrays. The candidate methylation markers were further refined through least absolute shrinkage and selection operator (LASSO) regression and Random Forest model. Besides, we investigate the functional role of ZNF573 in PCa. Our analysis identified four aging-related CpG sites in the promoter region of ZNF573 that exhibited significant hypermethylation in PCa. These four DNA methylation markers effectively distinguished PCa from benign prostatic hyperplasia (BPH) with high AUC (0.847), which was superior to PSA. Furthermore, the expression of ZNF573 was notably down-regulated in PCa, and its overexpression significantly inhibited PCa cells proliferation and invasion both in vivo and in vitro. ZNF573 acting as a transcription factor promoted the expression of the E3 ubiquitin ligase RNF19B, which regulated the ubiquitination of PIK3CA. These findings suggest that aging-related ZNF573 methylation could serve as a potential diagnostic biomarker for PCa, influencing the development and progression of PCa through the regulation of PIK3CA ubiquitination via RNF19B.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092176","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}

引用次数: 0

PRICKLE3-USP9X interaction-mediated DVL2 deubiquitination promotes the progression of non-small cell lung cancer via canonical WNT pathway. 针刺3- usp9x相互作用介导的DVL2去泛素化通过典型的WNT途径促进非小细胞肺癌的进展。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-19 DOI: 10.1038/s41388-025-03580-0

Mengdi Yang, Yudie Lu, Jingrong Zheng, Xinran Zhao, Guangping Wu, Enhua Wang, Huanyu Zhao

{"title":"PRICKLE3-USP9X interaction-mediated DVL2 deubiquitination promotes the progression of non-small cell lung cancer via canonical WNT pathway.","authors":"Mengdi Yang, Yudie Lu, Jingrong Zheng, Xinran Zhao, Guangping Wu, Enhua Wang, Huanyu Zhao","doi":"10.1038/s41388-025-03580-0","DOIUrl":"https://doi.org/10.1038/s41388-025-03580-0","url":null,"abstract":"Prickle planar cell polarity protein 3 (PRICKLE3) is involved in tumor malignant progression. However, little information is available regarding its detailed mechanism in non-small cell lung cancer (NSCLC). The clinicopathological significance of PRICKLE3 in NSCLC specimens was assessed. PRICKLE3-overexpression and PRICKLE3-knockout NSCLC cells were generated in vivo and in vitro. The interaction among PRICKLE3, ubiquitin-specific peptidase 9, X-chromosome (USP9X) and dishevelled2 (DVL2) in NSCLC cells was identified. We found that PRICKLE3 overexpression was correlated with advanced TNM stage, lymphatic metastasis, and poor prognosis in NSCLC patients. PRICKLE3 knockdown inhibited the viability, colony formation, and invasiveness in A549 and H1299 cells, and its overexpression promoted the viability, colony formation, and invasiveness in HBE, H460, and LK2 cells. PRICKLE3 promoted NSCLC growth in vivo. PRICKLE3-DVL2 interaction enhanced the β-catenin phosphorylation at serine 675 for β-catenin nuclear translocation. Furthermore, PRICKLE3 interacted with USP9X to inhibit the DVL2 ubiquitination for the DVL2 stability and the activation of canonical WNT signaling. Overall, we demonstrate a novel signal transduction pathway where PRICKLE3 interacts with USP9X and DVL2 to enhance the DVL2 deubiquitination mediated by USP9X for stabilizing DVL2 expression and activate the canonical WNT signaling for promoting the NSCLC progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092196","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}

引用次数: 0

Cancer-associated fibroblasts drive lung adenocarcinoma progression via THBS2-mediated epithelial-mesenchymal transition. 癌症相关成纤维细胞通过thbs2介导的上皮-间质转化驱动肺腺癌进展。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-19 DOI: 10.1038/s41388-025-03569-9

Yuqing Ren, Ruijie Ming, Anning Zuo, Shutong Liu, Yuhao Ba, Yuyuan Zhang, Yukang Chen, Teng Pan, Peng Luo, Quan Cheng, Jinhai Deng, Yi Yue, Hui Xu, Siyuan Weng, Xinwei Han, Dongdong Zhou, Zaoqu Liu

{"title":"Cancer-associated fibroblasts drive lung adenocarcinoma progression via THBS2-mediated epithelial-mesenchymal transition.","authors":"Yuqing Ren, Ruijie Ming, Anning Zuo, Shutong Liu, Yuhao Ba, Yuyuan Zhang, Yukang Chen, Teng Pan, Peng Luo, Quan Cheng, Jinhai Deng, Yi Yue, Hui Xu, Siyuan Weng, Xinwei Han, Dongdong Zhou, Zaoqu Liu","doi":"10.1038/s41388-025-03569-9","DOIUrl":"https://doi.org/10.1038/s41388-025-03569-9","url":null,"abstract":"The role of cancer-associated fibroblasts (CAFs) in the initiation and invasion phases of human lung adenocarcinoma (LUAD) development is not fully understood. In this study, we utilized single-cell RNA sequencing, spatial transcriptomics, and a combination of in vivo and in vitro models to decode the dynamics of tumor-stroma interactions during human LUAD progression, focusing primarily on adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). We identified a matrix CAF (mCAF) subtype characterized by high THBS2 expression, which was closely associated with poor clinical outcomes, tumor recurrence, and the invasive dynamics of LUAD. Spatial transcriptomics and multiplex immunohistochemistry analysis revealed that this CAF subpopulation was closely associated with tumor cells, with clear spatial colocalization. In vivo and in vitro experiments demonstrated that THBS2 secreted by these mCAFs directly binds to SDC4 on tumor cells, enhancing tumor epithelial-mesenchymal transition (EMT) programs. This study highlights THBS2+ mCAFs as key regulators of tumor-stroma interactions and identifies the THBS2-SDC4-EMT axis as a potential therapeutic target in LUAD.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092117","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}

引用次数: 0

Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer 雄激素受体及其蛋白相互作用组在去势抵抗性前列腺癌中的进化作用。

IF 7.3 1区医学

Oncogene Pub Date : 2025-09-18 DOI: 10.1038/s41388-025-03573-z

Muj Chukhu, Ujjwal R. Dahiya, Hannelore V. Heemers

{"title":"Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer","authors":"Muj Chukhu, Ujjwal R. Dahiya, Hannelore V. Heemers","doi":"10.1038/s41388-025-03573-z","DOIUrl":"10.1038/s41388-025-03573-z","url":null,"abstract":"The androgen receptor (AR) is a ligand-activated transcription factor that is a major driver of lethal prostate cancer (CaP) progression. Androgen deprivation therapy (ADT) that prevents the binding of androgens to AR has been the mainstay for the treatment of non-organ-confined CaP for more than 8 decades. Although ADT initially induces remissions, eventually resistance occurs while the majority of castration-resistant CaPs (CRPCs) continue to rely on AR’s action for growth. Sustained AR-dependence of CaP that recurs under ADT has historically been linked to AR’s transcriptional activity that controls expression of a distinct program of target genes that mediate aggressive behavior. Recently, less traditional transcriptional roles for AR, such as those impacting non-coding RNAs as well as transcription-independent roles that include AR-dependent splicing programs and translation control have been recognized to contribute to aggressive CaP features and treatment resistance. We reviewed and contrasted the contribution and relevance of these distinct functions for AR during CaP progression. We also considered the roles therein, both overlapping or mutually exclusive, for functionally diverse AR-interacting proteins that have been identified and to date have been mostly considered AR-associated transcriptional regulators. We discuss the potential implications of the involvement of AR interactors in multiple AR-dependent (non-)transcriptional cellular processes for alternative CaP treatment strategies that disrupt AR-coregulator interplay to inhibit AR-dependent transcription when AR ligand-deprivation has failed.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 41","pages":"3883-3894"},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03573-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086619","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}

引用次数: 0