Oncogene最新文献_第4页

Increased antiandrogen enzalutamide sensitivity via altering prostate cancer stem cell traits through modulating the androgen receptor-mediated CDR1/circCDR1-AS/miR-1290/BMP4 signaling. 通过调节雄激素受体介导的CDR1/circCDR1-AS/miR-1290/BMP4信号通路，通过改变前列腺癌干细胞特性，增加抗雄激素enzalutamide敏感性。

IF 6.9 1区医学

Oncogene Pub Date : 2025-07-04 DOI: 10.1038/s41388-025-03482-1

Diwei Huo, Minggui Si, Kexin Yu, Xiaoxue Fang, Hongbo Liu, Donglong Li, Zhengxing Chen, Jinguo Li, Ruicong Xu, Xinwang Su, Yongfeng Du, Xuebin Ma, Xunwei Wang, Pengbo Li, Huike Yang, Xiujie Chen, Keliang Wang

{"title":"Increased antiandrogen enzalutamide sensitivity via altering prostate cancer stem cell traits through modulating the androgen receptor-mediated CDR1/circCDR1-AS/miR-1290/BMP4 signaling.","authors":"Diwei Huo, Minggui Si, Kexin Yu, Xiaoxue Fang, Hongbo Liu, Donglong Li, Zhengxing Chen, Jinguo Li, Ruicong Xu, Xinwang Su, Yongfeng Du, Xuebin Ma, Xunwei Wang, Pengbo Li, Huike Yang, Xiujie Chen, Keliang Wang","doi":"10.1038/s41388-025-03482-1","DOIUrl":"https://doi.org/10.1038/s41388-025-03482-1","url":null,"abstract":"While the recent FDA-approved antiandrogen enzalutamide (Enz) might prolong the survival of castration-resistant prostate cancer (CRPC) patients by an additional 4.8 months, most patients eventually might still develop Enz resistance within 6-12 months. Although few genes have been linked to Enz resistance in prostate cancer (PCa), the detailed mechanism(s) are still underinvestigated. Here, we found that Enz might function by altering androgen receptor(AR)-mediated CDR1/circCDR1-AS/miR-1290/BMP4 signaling to modulate PCa stem cells (CSCs) to increase Enz resistance. Mechanistic analysis revealed that Enz/AR signaling can transcriptionally regulate CDR1 expression by reducing binding to androgen response elements (AREs) on the CDR1 5' promoter to alter circCDR1-AS expression. Enz/AR/CDR1/circCDR1-AS signaling might then increase BMP4 expression by altering miR-1290 expression, which involves direct binding to the 3' UTR of BMP4 mRNA. Preclinical studies using a CWR22Rv1 xenograft mouse model and integrative analysis of GEO cohort data further demonstrated that targeting this newly identified Enz/AR/CDR1/circCDR1-AS/miR-1290/BMP4 signaling pathway with miR-1290, circCDR1-AS-shRNA, or BMP4-shRNA may help develop novel therapies to combat Enz resistance at the later stage of CRPC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565065","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

Impaired autophagy by cepharanthine induces immunogenic cell death and enhances anti-PD-1 response in MSS-type colorectal cancer. 在mss型结直肠癌中，头蒽醌诱导免疫原性细胞死亡并增强抗pd -1反应。

IF 6.9 1区医学

Oncogene Pub Date : 2025-07-03 DOI: 10.1038/s41388-025-03488-9

Ming Zhao, Juan Nie, Ao Ye, Chang Liu, Xuemei Li, Ziyi Yang, Runyu Zhou, Jun Li, Chuan Xu

{"title":"Impaired autophagy by cepharanthine induces immunogenic cell death and enhances anti-PD-1 response in MSS-type colorectal cancer.","authors":"Ming Zhao, Juan Nie, Ao Ye, Chang Liu, Xuemei Li, Ziyi Yang, Runyu Zhou, Jun Li, Chuan Xu","doi":"10.1038/s41388-025-03488-9","DOIUrl":"https://doi.org/10.1038/s41388-025-03488-9","url":null,"abstract":"Blockade of the PD-1/PD-L1 axis has demonstrated remarkable success in treating colorectal cancer (CRC) with high microsatellite instability (MSI-H). However, the metastatic CRC with microsatellite stability (MSS) does not respond to this approach. A recent study revealed that rare neoantigens in MSS-type CRC cells can be recognized by antigen-specific CD8+ T cells but not by dendritic cells (DCs). Thus, increasing neoantigen availability by DCs may improve the efficacy of PD-1/PD-L1 inhibitors in MSS-type CRC. Here, we conducted a drug library screening for 'eat me' signal, represented by cell surface calreticulin (CRT) exposure, in MSS-type CT26 cells. Cells treated with identified cepharanthine (CEP) presented hallmarks of immunogenic cell death (ICD), characterized by increased cell surface CRT exposure, the release of HMGB1 and ATP, increased susceptibility to phagocytosis, and the ability of vaccines to elicit immunogenic potential in vivo. Mechanistically, CEP blocked autophagic flux by inhibiting autophagsome-lysosome fusion, leading to endoplasmic reticulum (ER) stress and ICD activation. Moreover, CEP upregulated PD-L1 expression on tumour cells, impeding the antitumour immune response in vivo. The combination of CEP and anti-PD-1 therapy provided therapeutic benefit to MSS-type CRC tumours, with an increased proportion of activated DCs and IFNγ+ CD8+ T cells and a decreased proportion of regulatory T cells within the tumour. Based on the above observation, subsequent clinical trials can be conducted to achieve the clinical goal of increasing the survival benefit of MSS-CRC patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560710","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

The interplay between oxytocin receptor and YAP in regulating gastric cancer progression. 催产素受体与YAP在调节胃癌进展中的相互作用。

IF 6.9 1区医学

Oncogene Pub Date : 2025-07-02 DOI: 10.1038/s41388-025-03480-3

Ziping Liu, Honghu Wang, Chenmiao Zhang, Hao Qi, Zhongbo Li, Yanan Sun, Beibei Wang, Fangyu Shen, Zehao Hong, Jian Zhu, Xin Li, Yinlu Ding, Kai Li

{"title":"The interplay between oxytocin receptor and YAP in regulating gastric cancer progression.","authors":"Ziping Liu, Honghu Wang, Chenmiao Zhang, Hao Qi, Zhongbo Li, Yanan Sun, Beibei Wang, Fangyu Shen, Zehao Hong, Jian Zhu, Xin Li, Yinlu Ding, Kai Li","doi":"10.1038/s41388-025-03480-3","DOIUrl":"https://doi.org/10.1038/s41388-025-03480-3","url":null,"abstract":"Gastric cancer (GC) remains a lethal malignancy with limited therapeutic targets, while recent studies revealed YAP could be a promising target for GC treatment. In our study, we identify oxytocin receptor (OXTR) as an important regulator of Hippo/YAP axis. Through bioinformatics analysis, RNA sequencing analysis, functional research, and molecular mechanism research, we found that OXTR could facilitate Hippo/YAP axis, while YAP were shown to bind the OXTR promoter, enhancing its expression and establishing an interesting positive feedback loop. These findings propose the significance of OXTR in GC progression and its potential as a therapeutic target for YAP-driven cancer. Schematic representation of the interaction between OXTR and the Hippo-YAP pathway: The activation of OXTR leads to the formation of a complex with ARRB2, thereby outcompeting LATS1 and inhibiting its phosphorylation of YAP. This interaction increases YAP signaling activity, which in turn promotes the progression of gastric cancer. Furthermore, YAP can bind to the promoter region of OXTR, facilitating its expression and establishing a positive feedback loop. The use of the OXTR antagonist Atosiban to inhibit OXTR activity promotes the phosphorylation of LATS1 by ARRB2, which subsequently suppresses YAP phosphorylation. This results in the sequestration of YAP in the cytoplasm, thereby inhibiting the progression of gastric cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554064","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

Integrative epigenome and transcriptome analyses reveal transcriptional programs differentially regulated by ASCL1 and NEUROD1 in small cell lung cancer. 综合表观基因组和转录组分析揭示了ASCL1和NEUROD1在小细胞肺癌中的转录程序差异调控。

IF 6.9 1区医学

Oncogene Pub Date : 2025-07-01 DOI: 10.1038/s41388-025-03481-2

Hiroshi Takumida, Akira Saito, Yugo Okabe, Yasuhiro Terasaki, Yu Mikami, Hidenori Tanaka, Masami Suzuki, Yu Hamaguchi, Chao Zeng, Michiaki Hamada, Hiroshi I Suzuki, Hidenori Kage, Masafumi Horie

{"title":"Integrative epigenome and transcriptome analyses reveal transcriptional programs differentially regulated by ASCL1 and NEUROD1 in small cell lung cancer.","authors":"Hiroshi Takumida, Akira Saito, Yugo Okabe, Yasuhiro Terasaki, Yu Mikami, Hidenori Tanaka, Masami Suzuki, Yu Hamaguchi, Chao Zeng, Michiaki Hamada, Hiroshi I Suzuki, Hidenori Kage, Masafumi Horie","doi":"10.1038/s41388-025-03481-2","DOIUrl":"https://doi.org/10.1038/s41388-025-03481-2","url":null,"abstract":"Small cell lung cancer (SCLC), an aggressive neuroendocrine carcinoma, has an extremely poor prognosis. ASCL1 and NEUROD1 are key regulators of neuroendocrine features, and previous studies have suggested that SCLC plasticity occurs during the transition from ASCL1-positive (SCLC-A) to NEUROD1-positive (SCLC-N) subtypes. In this study, we attempted to understand the transcriptional programs governed by ASCL1 and NEUROD1 to identify markers of SCLC plasticity. Immunohistochemistry and epigenome and transcriptome analyses in ASCL1/NEUROD1 double-positive SCLC cells (SCLC-A/N) revealed co-expression of ASCL1 and NEUROD1 in almost half of SCLC cases. Genome-wide profiling of histone modifications, ASCL1 and NEUROD1 binding sites, and gene co-expression patterns revealed that both ASCL1 and NEUROD1 are active in SCLC-A/N and regulate partially distinct target genes. Furthermore, SCLC-A/N exhibited characteristics that were intermediate between SCLC-A and SCLC-N subtypes. NEUROD1 knockout, followed by RNA-seq, suggested an association between NEUROD and NHLH transcription factors that might shape the NEUROD1-mediated regulatory network. Small RNA-seq further indicated that miR-139-5p is specifically expressed in NEUROD1-positive SCLC, and transcriptomic studies suggested that miR-139-5p might regulate an array of pathologically relevant genes in collaboration with other NEUROD1-associated miRNAs. Our integrative analyses provide deeper insights into SCLC heterogeneity and multi-layered transcriptional programs differentially governed by ASCL1 and NEUROD1.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144541677","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

ACSL5 regulated acetyl-CoA to promote bladder cancer cellular senescence via 53BP1 acetylation. ACSL5通过53BP1乙酰化调控乙酰辅酶a促进膀胱癌细胞衰老。

IF 6.9 1区医学

Oncogene Pub Date : 2025-07-01 DOI: 10.1038/s41388-025-03474-1

Yongbo Luo, Youmiao Zeng, Yuanhao Liu, Sheng Liu, Yiheng Dai, Wenbang Pan, Lailai Zhang, Ronghui Zhu, Dapeng Feng, Kaixuan Du, Xuepei Zhang, Bin Jia, Fengyan Tian, Lijie Zhou, Chaohui Gu

{"title":"ACSL5 regulated acetyl-CoA to promote bladder cancer cellular senescence via 53BP1 acetylation.","authors":"Yongbo Luo, Youmiao Zeng, Yuanhao Liu, Sheng Liu, Yiheng Dai, Wenbang Pan, Lailai Zhang, Ronghui Zhu, Dapeng Feng, Kaixuan Du, Xuepei Zhang, Bin Jia, Fengyan Tian, Lijie Zhou, Chaohui Gu","doi":"10.1038/s41388-025-03474-1","DOIUrl":"https://doi.org/10.1038/s41388-025-03474-1","url":null,"abstract":"Disruption of the fatty acid oxidation process (FAO) significantly affects the tumorigenesis of bladder cancer (BC). We found that long-chain fatty acid synthase 5 (ACSL5) acting as a key enzyme in the initial stage of FAO, was downregulated in BC, and the decreased level of ACSL5 was strongly associated with a poor prognosis for BC patients. Mechanistically, ACSL5 is highly methylated CpG islands in its DNA, which is regulated by DNA methyltransferase 1 (DNMT1). ACSL5 promotes FAO, and reduces the intracellular lipid content while increasing the level of acetyl-CoA. Acetyl-CoA improves K1360 acetylation of TP53-binding protein 1 (53BP1), subsequently enhancing the recruitment of the P53-P21 senescent signaling axis in the nucleus and promoting cellular senescence. ACSL5 overexpression promoted BC senescence and inhibited BC cell proliferation, and elaidic acid (EA) feeding further enhanced these effects in vitro and in vivo. In summary, our study revealed that ACSL5-mediated lipid oxidation increases the acetyl-CoA content, promotes cellular senescence, and inhibits the proliferation of BC. The activation of ACSL5-mediated lipid oxidation to regulate cellular senescence may provide an innovative direction for BC therapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144541676","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

ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer. ZMYND8在胰腺癌中通过c-Myc激活促进Warburg效应和肿瘤发生。

IF 6.9 1区医学

Oncogene Pub Date : 2025-06-27 DOI: 10.1038/s41388-025-03483-0

Hui Liu, Zhifeng Zhao, Changle Wu, Jinxin Chen, Zhiwei He, Kai Jiang

{"title":"ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer.","authors":"Hui Liu, Zhifeng Zhao, Changle Wu, Jinxin Chen, Zhiwei He, Kai Jiang","doi":"10.1038/s41388-025-03483-0","DOIUrl":"https://doi.org/10.1038/s41388-025-03483-0","url":null,"abstract":"Pancreatic cancer (PC) is a digestive tract tumour with an extremely poor patient prognosis and prominent metabolic abnormalities. However, the molecular mechanisms underlying metabolic reprogramming in the progression of pancreatic cancer remain poorly understood. Here, we employed an epigenetic siRNA library to identify a crucial regulator, ZMYND8, which is involved in glycolysis in PC cells. ZMYND8 was frequently overexpressed in both PC tissues and cell lines, and its elevated expression was significantly correlated with poor overall survival in patients with PC. The high rates of glucose uptake and lactate secretion conferred by ZMYND8 revealed an abnormal activity of aerobic glycolysis in PC cells. Functional studies revealed that ZMYND8 significantly promoted the proliferation, migration and invasion of PC cells. Integrated analyses of CUT&Tag and RNA-seq data revealed that ZMYND8 may activate c-Myc transcriptional activity by modulating downstream epigenetic regulatory pathways. Proteomic profiling and coimmunoprecipitation (Co-IP) assays further demonstrated a direct physical interaction between ZMYND8 and c-Myc. Mechanistic studies revealed that ZMYND8 interacted with and activated c-Myc, thereby promoting the Warburg effect and facilitating PC cell malignancy. Moreover, in vivo studies revealed that overexpression of ZMYND8 resulted in accelerated tumour growth in PC xenografts, which was reversible through the knockdown of c-Myc or treatment with 2-deoxy-D-glucose. Collectively, our data suggest that ZMYND8 functions as a critical metabolic regulator in PC cells by tightly regulating c-Myc activity and may represent a promising novel therapeutic target for advanced pancreatic cancer treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512257","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

Correction: Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis 更正：缺氧通过USP2-NCOA4轴抑制食道鳞状细胞癌中铁蛋白吞噬介导的铁下垂。

IF 6.9 1区医学

Oncogene Pub Date : 2025-06-27 DOI: 10.1038/s41388-025-03443-8

Jiahang Song, Junfeng Zhang, Yujing Shi, Qing Gao, Hui Chen, Xiaofeng Ding, Minghui Zhao, Caiqiang Zhu, Liang Liang, Xinchen Sun, Yingyin Zhu, Wei Wang, Qing Li, Xiaoke Di

引用次数: 0

PR55α subunit of protein phosphatase 2A supports KRAS^G12D-driven tumorigenesis that requires YAP activation. 蛋白磷酸酶2A的PR55α亚基支持krasg12d驱动的肿瘤发生，这需要YAP激活。

IF 6.9 1区医学

Oncogene Pub Date : 2025-06-26 DOI: 10.1038/s41388-025-03477-y

Christopher B Jenkins, Alison L Camero, Brendan T Graff, Lepakshe S V Madduri, Kelly A O'Connell, Ashley L Hein, Lynette M Smith, Charles A Enke, Jixin Dong, Michael A Hollingsworth, Keith R Johnson, Michel M Ouellette, Ying Yan

{"title":"PR55α subunit of protein phosphatase 2A supports KRASG12D-driven tumorigenesis that requires YAP activation.","authors":"Christopher B Jenkins, Alison L Camero, Brendan T Graff, Lepakshe S V Madduri, Kelly A O'Connell, Ashley L Hein, Lynette M Smith, Charles A Enke, Jixin Dong, Michael A Hollingsworth, Keith R Johnson, Michel M Ouellette, Ying Yan","doi":"10.1038/s41388-025-03477-y","DOIUrl":"10.1038/s41388-025-03477-y","url":null,"abstract":"PP2A holoenzymes account nearly 50% of Ser/Thr phosphatase activities in human cells, yet their roles in oncogenesis remain largely unexplored. A PP2A holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. We previously reported that PR55α, a PP2A regulatory subunit, supports the tumorigenic and metastatic potential of pancreatic cancer cells, and this is associated with its role in promoting YAP activation, which is essential for tumorigenesis and progression in most solid tumors, including pancreatic cancer. However, the direct role of PR55α in tumorigenesis has not yet been assessed. Using telomerase-immortalized human pancreatic ductal cells (HPNE), this research reveals a mechanism in which PR55α/PP2A cooperates with oncogenic KRASG12D to drive cellular transformation and tumorigenesis in vivo. HPNE-transduced with PR55α and KRASG12D exhibited accelerated proliferation and migration, and anchorage-independent growth, hallmark features of malignant transformation. Biochemical studies demonstrated that PR55α-induced YAP activation was further enhanced by KRASG12D, primarily through the inhibition of the MST/LATS cascade. The essential role of YAP activation in HPNE transformation by PR55α and KRASG12D was confirmed by YAP inhibition. Finally, in vivo studies revealed that HPNE cells transformed by PR55α and KRASG12D were tumorigenic in mice. Collectively, these findings highlight the critical role of PR55α/PP2A in supporting KRAS-driven tumorigenesis, providing new insights into the mechanisms underlying pancreatic cancer progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507314","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

RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer. RBM5以三明治模式招募MGC32805，诱导ΔFAS新抗原并触发FAS特性转换：在结直肠癌中的意义

IF 6.9 1区医学

Oncogene Pub Date : 2025-06-26 DOI: 10.1038/s41388-025-03390-4

Huizhe Wu, Xiaoyun Hu, Yilin Wang, Xianglong Zhu, Qing Zhao, Yingqi Zhao, Wanlin Cui, Mingrong Zhang, Haishan Zhao, Kai Li, Minjie Wei

{"title":"RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer.","authors":"Huizhe Wu, Xiaoyun Hu, Yilin Wang, Xianglong Zhu, Qing Zhao, Yingqi Zhao, Wanlin Cui, Mingrong Zhang, Haishan Zhao, Kai Li, Minjie Wei","doi":"10.1038/s41388-025-03390-4","DOIUrl":"https://doi.org/10.1038/s41388-025-03390-4","url":null,"abstract":"Pre-mRNA alternative splicing (AS) is a crucial process, which plays a significant role in inducing tumor subtype-specific alterations and the hallmark of epigenetic heterogeneity in tumorigenesis. However, the regulatory mechanisms of pre-mRNA AS remain obscure. This study demonstrates that splicing factor RBM5 recruits long non-coding RNA MGC32805, and they act in concert as oncogenes in colorectal cancer (CRC) cells by preventing apoptosis, as well as promoting migration and resistance to 5-Fluorouracil (5-FU). Specifically, they promote the exclusion of exon 6 in the FAS pre-mRNA, leading to decreased expression of mFAS (an apoptotic isoform) and increased expression of ΔFAS (an anti-apoptotic isoform) in both CRC cells and a mouse xenograft model. RBM5, which contains Leu650 and Arg681 residues in the ZnF-C2H2 domain, recognizes the \"GUACG\" (-1299 to -1303) motif in MGC32805. Furthermore, MGC32805 blocks the binding site (Lys645) of the E3 ubiquitin ligase PRPF19, which targets RBM5 for degradation, thus increasing the stability of RBM5. The His665 and Leu668 residues of RBM5 specifically bind to the FAS exon 6 adjacent element (GAACAAA), which drives FAS-AS events and increases the expression ratio of the ΔFAS/mFAS isoforms. These findings introduce a novel research strategy to investigate the epigenetic heterogeneity and plasticity of tumorigenesis. They also shed light on the mechanism of MGC32805-mediated transformation of the FAS tumor neoantigen function from a tumor suppressor to an oncogene at the AS level through its interactions with RBM5.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507315","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

Post-transcriptional control of gene expression by β-catenin: expanding the non-canonical ARMoury β-catenin对基因表达的转录后调控：扩展非规范军械库。

IF 6.9 1区医学

Oncogene Pub Date : 2025-06-25 DOI: 10.1038/s41388-025-03470-5

O. Sevim, H. Park, R. G. Morgan

{"title":"Post-transcriptional control of gene expression by β-catenin: expanding the non-canonical ARMoury","authors":"O. Sevim, H. Park, R. G. Morgan","doi":"10.1038/s41388-025-03470-5","DOIUrl":"10.1038/s41388-025-03470-5","url":null,"abstract":"The Wnt/β-catenin pathway is an evolutionarily conserved signal transduction cascade with critical regulatory roles in cellular proliferation, cell fate determination and tissue homeostasis. Through the regulation of multiple human stem cell systems, canonical Wnt signalling is not only a major contributor to normal development, but also heavily implicated in a multitude of human diseases, including cancer. The central mediator of the pathway β-catenin, first identified as Armadillo (ARM) in Drosophila, has well-defined roles in cell adhesion and transcription within the pathway. However, accumulating evidence suggests β-catenin functionality is more complex than initially anticipated with reported roles beyond those historically characterised, including the regulation of RNA and RNA-binding proteins (RBP). This review will summarise the current understanding around β-catenin as a post-transcriptional regulator in normal and malignant development, drawing particular attention to cell types not traditionally used to characterise Wnt signalling but uniquely placed to reveal novel β-catenin function.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 29","pages":"2453-2459"},"PeriodicalIF":6.9,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03470-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497582","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