Oncogene最新文献

{"title":"MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation","authors":"Rosa Bordone, Devon Michael Ivy, Rodrigo D’Amico, Martina Barba, Miriam Gaggianesi, Fiorella Di Pastena, Bianca Cesaro, Francesca Bufalieri, Alessio Balzerano, Enrico De Smaele, Giuseppe Giannini, Lucia Di Marcotullio, Alessandro Fatica, Giorgio Stassi, Laura Di Magno, Sonia Coni, Gianluca Canettieri","doi":"10.1038/s41388-024-03170-6","DOIUrl":"10.1038/s41388-024-03170-6","url":null,"abstract":"The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 46","pages":"3349-3365"},"PeriodicalIF":6.9,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03170-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292689","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":"SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways","authors":"Xiaolin Sang, Jiaxin Han, Zhaojing Wang, Weiji Cai, Xingming Liao, Zhuolin Kong, Zhijie Yu, Hailing Cheng, Pixu Liu","doi":"10.1038/s41388-024-03173-3","DOIUrl":"10.1038/s41388-024-03173-3","url":null,"abstract":"High-grade serous ovarian cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to ferroptosis, as shown by increased PTGS2 expression (a ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of ferroptosis and suggest targeting SGK1 alongside ferroptosis pathways as a potential therapeutic strategy for HGSOC patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 45","pages":"3335-3347"},"PeriodicalIF":6.9,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03173-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292690","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":"The TβRI promotes migration and metastasis through thrombospondin 1 and ITGAV in prostate cancer cells","authors":"Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, André Mateus, Maréne Landström","doi":"10.1038/s41388-024-03165-3","DOIUrl":"10.1038/s41388-024-03165-3","url":null,"abstract":"TGFβ potently modifies the extracellular matrix (ECM), which is thought to favor tumor cell invasion. However, the mechanism whereby the cancer cells employ the ECM proteins to facilitate their motility is largely unknown. In this study we used RNA-seq and proteomic analysis to examine the proteins secreted by castration-resistant prostate cancer (CRPC) cells upon TGFβ treatment and found that thrombospondin 1 (THBS1) was observed to be one of the predominant proteins. The CRISPR Cas9, or siRNA techniques was used to downregulate TGFβ type I receptor (TβRI) to interfere with TGFβ signaling in various cancer cells in vitro. The interaction of ECM proteins with the TβRI in the migratory prostate cancer cells in response to TGFβ1 was demonstrated by several different techniques to reveal that THBS1 mediates cell migration by interacting with integrin subunit alpha V (ITGAV) and TβRI. Deletion of TβRI or THBS1 in cancer cells prevented their migration and invasion. THBS1 belongs to a group of tumorigenic ECM proteins induced via TGFβ signaling in CRPC cells, and high expression of THBS1 in human prostate cancer tissues correlated with the degree of malignancy. TGFβ-induced production of THBS1 through TβRI facilitates the invasion and metastasis of CRPC cells as shown in vivo xenograft animal experiments.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 45","pages":"3321-3334"},"PeriodicalIF":6.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03165-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292691","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":"Editorial Expression of Concern: Role of BRCA1 in heat shock response","authors":"Yong Xian Ma, Saijun Fan, Jingbo Xiong, Ren-qi Yuan, Qinghui Meng, Min Gao, Itzhak D. Goldberg, Suzanne A. Fuqua, Richard G. Pestell, Eliot M. Rosen","doi":"10.1038/s41388-024-03168-0","DOIUrl":"10.1038/s41388-024-03168-0","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 43","pages":"3214-3214"},"PeriodicalIF":6.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03168-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292687","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":"Kindlin-2 regulates the oncogenic activities of integrins and TGF-β in triple-negative breast cancer progression and metastasis","authors":"Neelum Aziz Yousafzai, Lamyae El Khalki, Wei Wang, Justin Szpendyk, Khalid Sossey-Alaoui","doi":"10.1038/s41388-024-03166-2","DOIUrl":"10.1038/s41388-024-03166-2","url":null,"abstract":"Kindlin-2, an adapter protein, is dysregulated in various human cancers, including triple-negative breast cancer (TNBC), where it drives tumor progression and metastasis by influencing several cancer hallmarks. One well-established role of Kindlin-2 involves the regulation of integrin signaling, achieved by directly binding to the cytoplasmic tail of the integrin β subunit. In this study, we present novel insights into Kindlin-2’s involvement in stabilizing the β1-Integrin:TGF-β type 1 receptor (TβRI) complexes, acting as a physical bridge that links β1-Integrin to TβRI. Loss of Kindlin-2 results in the degradation of this protein complex, leading to the inhibition of downstream oncogenic pathways. We used a diverse range of in vitro assays, including CRISPR/Cas9 gene editing, cell migration, 3D-tumorsphere formation and invasion, solid binding, co-immunoprecipitation, cell adhesion and spreading assays, as well as western blot and flow cytometry analyses, utilizing MDA-MB-231 and 4T1 TNBC cell lines. Additionally, preclinical in vivo mouse models of TNBC tumor progression and metastasis were employed to substantiate our findings. Our studies established the direct interaction between Kindlin-2 and β1-Integrin and between Kindlin-2 and TβRI. Disruption of these interactions, via CRISPR/Cas9-mediated knockout of Kindlin-2, led to the degradation of β1-Integrin and TβRI, resulting in the inhibition of oncogenic pathways downstream of both proteins, subsequently hindering tumor growth and metastasis. Treatment of Kindlin-2-deficient cells with the proteasome inhibitor MG-132 restored the expression of both β1-Integrin and TβRI. Furthermore, the rescue of Kindlin-2 expression reinstated their oncogenic activities in vitro and in vivo, while Kindlin-2 lacking domains involved in the interaction of Kindlin-2 with β1-Integrin or TβRI did not. This study identifies a novel function of Kindlin-2 in stabilizing the β1-Integrin:TβRI complexes and regulating their downstream oncogenic signaling. The translational implications of these findings are substantial, potentially unveiling new therapeutically targeted pathways crucial for the treatment of TNBC tumors.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 45","pages":"3291-3305"},"PeriodicalIF":6.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03166-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292688","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":"SUV39H1 epigenetically modulates the MCPIP1-AURKA signaling axis to enhance neuroblastoma tumorigenesis","authors":"Mengzhen Li, Feifei Sun, Juan Wang, Suying Lu, Yi Que, Mengjia Song, Huimou Chen, Xiangyu Xiong, Weiji Xie, Jia Zhu, Junting Huang, Yu Zhang, Yizhuo Zhang","doi":"10.1038/s41388-024-03164-4","DOIUrl":"10.1038/s41388-024-03164-4","url":null,"abstract":"Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 45","pages":"3306-3320"},"PeriodicalIF":6.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03164-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252740","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":"NUP37 accumulation mediated by TRIM28 enhances lipid synthesis to accelerate HCC progression","authors":"Zhiyi Liu, Qinghe Hu, Qing Luo, Guowei Zhang, Weichao Yang, Kuan Cao, Ruqiao Fang, Renhao Wang, Hengliang Shi, Bin Zhang","doi":"10.1038/s41388-024-03167-1","DOIUrl":"10.1038/s41388-024-03167-1","url":null,"abstract":"Elevated intracellular lipid synthesis is important for hepatocellular carcinoma (HCC) progression. Our study aimed to identify the role of nucleoporin 37 (NUP37) in lipid synthesis and HCC progression. The expression of NUP37 was significantly upregulated in HCC and associated with a poor prognosis. NUP37 silencing suppressed lipid synthesis, proliferation, migration, and invasion of HCC cells in vitro, and restrained tumor growth in xenograft mouse models in vivo. Next, we found the high expression of NUP37 in HCC was related to post-translational modifications. Tripartite motif-containing 28 (TRIM28) was identified as an interacting protein of NUP37 and upregulated its protein level. The subsequent analysis revealed that TRIM28-mediated SUMOylation of NUP37 at Lys114/118/246 inhibited K27-linked polyubiquitination of NUP37, which is one reason for its high expression level in HCC. In conclusion, TRIM28 SUMOylates NUP37 to prevent its ubiquitination and proteasomal degradation, increasing the stability of the NUP37 protein, thereby promoting lipid synthesis and the progression of HCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 44","pages":"3255-3267"},"PeriodicalIF":6.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268620","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":"The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer","authors":"Wenbo Tang, Yiqing Yang, Zhuoyue Fu, Weimin Xu, Weijun Ou, Fangyuan Liu, Peng Du, Chen-Ying Liu","doi":"10.1038/s41388-024-03160-8","DOIUrl":"10.1038/s41388-024-03160-8","url":null,"abstract":"The RNA helicase DDX21 is vital for ribosome biogenesis and is upregulated in CRC, but the mechanism by which DDX21 is dysregulated and by which DDX21 promotes tumorigenesis in CRC remains poorly understood. Here, we showed that DDX21 is a direct transcriptional target gene of β-catenin and mediates the protumorigenic function of β-catenin in CRC. DDX21 expression is correlated with the expression and activity of β-catenin, and high DDX21 expression is associated with a poor prognosis in CRC patients. Loss of DDX21 leads to cytoplasmic translocation and decreased transcriptional activity of YAP and suppresses the proliferation and migration of CRC cells, which can be partially rescued by YAP reactivation. Importantly, by using translation elongation inhibitors and DNA intercalators, we showed that ribosomal stress upregulates DDX21 expression and induces the downregulation of LATS and the activation of YAP, probably through the ZAKα-MKK4/7-JNK axis. Overall, our study revealed the transcriptional activation mechanism of DDX21 in CRC and the activation of YAP in the ribosomal stress response, indicating the potential of combination therapy involving the induction of ribosomal stress and YAP inhibition.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 44","pages":"3227-3239"},"PeriodicalIF":6.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03160-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252741","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":"DDX5 promotes esophageal squamous cell carcinoma growth through sustaining VAV3 mRNA stability","authors":"Yunshu Shi, Junyong Wang, Qiang Yuan, Yingying Chen, Miao Zhao, Xiaoyu Li, Zitong Wang, Hao Zhou, Fangli Zhu, Bing Wei, Yanan Jiang, Jimin Zhao, Yan Qiao, Zigang Dong, Kangdong Liu","doi":"10.1038/s41388-024-03162-6","DOIUrl":"10.1038/s41388-024-03162-6","url":null,"abstract":"Novel therapeutic targets and their inhibitors for esophageal squamous cell carcinoma (ESCC) prevention and therapy are urgently needed. This study aimed to investigate the function of DEAD-box helicase 5 (DDX5) in ESCC progression and to identify a promising inhibitor of DDX5. We verified that DDX5 was highly expressed in ESCC and played an oncogenic role, binding with vav guanine nucleotide exchange factor 3 (VAV3) mRNA and facilitating VAV3 mRNA N6-methyladenosine (m6A) modification by interacting with the m6A methyltransferase 3 (METTL3). M6A-modified VAV3 mRNA was identified by insulin-like growth factor 1 (IGF2BP1), increasing mRNA stability. Methylnissolin-3-β-D-O-glucoside (MD) inhibited ESCC progression through the DDX5-VAV3 axis. Our findings suggest that DDX5 promotes ESCC progression. MD inhibits ESCC progression by targeting DDX5.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 44","pages":"3240-3254"},"PeriodicalIF":6.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03162-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252747","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":"The tumor suppressor Parkin exerts anticancer effects through regulating mitochondrial GAPDH activity","authors":"Xin Sun, Guiqin Ye, Jiuzhou Li, Liyang Yuan, Gongxun Bai, Yong-Jiang Xu, Jianbin Zhang","doi":"10.1038/s41388-024-03157-3","DOIUrl":"10.1038/s41388-024-03157-3","url":null,"abstract":"Cancer cells preferentially utilize glycolysis for energy production, and GAPDH is a critical enzyme in glycolysis. Parkin is a tumor suppressor and a key protein involved in mitophagy regulation. However, the tumor suppression mechanism of Parkin has still not been elucidated. In this study, we identified mitochondrial GAPDH as a new substrate of the E3 ubiquitin ligase Parkin, which mediated GAPDH ubiquitination in human cervical cancer. The translocation of GAPDH into mitochondria was driven by the PINK1 kinase, and either PINK1 or GAPDH mutation prevented the accumulation of GAPDH in mitochondria. Parkin caused the ubiquitination of GAPDH at multiple sites (K186, K215, and K219) located within the enzyme-catalyzed binding domain of the GAPDH protein. GAPDH ubiquitination was required for mitophagy, and stimulation of mitophagy suppressed cervical cancer cell growth, indicating that mitophagy serves as a type of cell death. Mechanistically, PHB2 served as a key mediator in GAPDH ubiquitination-induced mitophagy through stabilizing PINK1 protein and GAPDH mutation resulted in the reduced distribution of PHB2 in mitophagic vacuole. In addition, ubiquitination of GAPDH decreased its phosphorylation level and enzyme activity and inhibited the glycolytic pathway in cervical cancer cells. The results of in vivo experiments also showed that the GAPDH mutation increased glycolysis in cervical cancer cells and accelerated tumorigenesis. Thus, we concluded that Parkin may exert its anticancer function by ubiquitinating GAPDH in mitochondria. Taken together, our study further clarified the molecular mechanism of tumor suppression by Parkin through the regulation of energy metabolism, which provides an experimental basis for the development of new drugs for the treatment of human cervical cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 44","pages":"3215-3226"},"PeriodicalIF":6.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03157-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252742","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}