Oncogenesis最新文献

{"title":"LUBAC promotes angiogenesis and lung tumorigenesis by ubiquitinating and antagonizing autophagic degradation of HIF1α","authors":"Ying Jin, Yazhi Peng, Jie Xu, Ye Yuan, Nan Yang, Zemei Zhang, Lei Xu, Lin Li, Yulian Xiong, Dejiao Sun, Yamu Pan, Ruiqing Wu, Jian Fu","doi":"10.1038/s41389-024-00508-3","DOIUrl":"https://doi.org/10.1038/s41389-024-00508-3","url":null,"abstract":"<p>Hypoxia-inducible factor 1 (HIF1) is critically important for driving angiogenesis and tumorigenesis. Linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin ligase capable of catalyzing protein linear ubiquitination to date, is implicated in cell signaling and associated with cancers. However, the role and mechanism of LUBAC in regulating the expression and function of HIF1α, the labile subunit of HIF1, remain to be elucidated. Herein we showed that LUBAC increases HIF1α protein expression in cultured cells and tissues of human lung cancer and enhances HIF1α DNA-binding and transcriptional activities, which are dependent upon LUBAC enzymatic activity. Mechanistically, LUBAC increases HIF1α stability through antagonizing HIF1α decay by the chaperone-mediated autophagy (CMA)-lysosome pathway, thereby potentiating HIF1α activity. We further demonstrated that HIF1α selectively interacts with HOIP (the catalytic subunit of LUBAC) primarily in the cytoplasm. LUBAC catalyzes linear ubiquitination of HIF1α at lysine 362. Linear ubiquitination shields HIF1α from interacting with heat-shock cognate protein of 70 kDa and lysosome-associated membrane protein type 2 A, two components of CMA. Consequently, linear ubiquitination confers protection against CMA-mediated destruction of HIF1α, increasing HIF1α stability and activity. We found that prolyl hydroxylation is not a perquisite for LUBAC’s effects on HIF1α. Functionally, LUBAC facilitates proliferation, clonogenic formation, invasion and migration of lung cancer cells. LUBAC also boosts angiogenesis and exacerbates lung cancer growth in mice, which are greatly compromised by inhibition of HIF1α. This work provides novel mechanistic insights into the role of LUBAC in regulating HIF1α homeostasis, tumor angiogenesis and tumorigenesis of lung cancer, making LUBAC an attractive therapeutic target for cancers.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"34 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139552430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preneoplastic cells switch to Warburg metabolism from their inception exposing multiple vulnerabilities for targeted elimination.","authors":"Henna Myllymäki, Lisa Kelly, Abigail M Elliot, Roderick N Carter, Jeanette Astorga Johansson, Kai Yee Chang, Justyna Cholewa-Waclaw, Nicholas M Morton, Yi Feng","doi":"10.1038/s41389-024-00507-4","DOIUrl":"10.1038/s41389-024-00507-4","url":null,"abstract":"<p><p>Otto Warburg described tumour cells as displaying enhanced aerobic glycolysis whilst maintaining defective oxidative phosphorylation (OXPHOS) for energy production almost 100 years ago [1, 2]. Since then, the 'Warburg effect' has been widely accepted as a key feature of rapidly proliferating cancer cells [3-5]. What is not clear is how early \"Warburg metabolism\" initiates in cancer and whether changes in energy metabolism might influence tumour progression ab initio. We set out to investigate energy metabolism in the HRAS^G12V driven preneoplastic cell (PNC) at inception, in a zebrafish skin PNC model. We find that, within 24 h of HRAS^G12V induction, PNCs upregulate glycolysis and blocking glycolysis reduces PNC proliferation, whilst increasing available glucose enhances PNC proliferation and reduces apoptosis. Impaired OXPHOS accompanies enhanced glycolysis in PNCs, and a mild complex I inhibitor, metformin, selectively suppresses expansion of PNCs. Enhanced mitochondrial fragmentation might be underlining impaired OXPHOS and blocking mitochondrial fragmentation triggers PNC apoptosis. Our data indicate that altered energy metabolism is one of the earliest events upon oncogene activation in somatic cells, which allows a targeted and effective PNC elimination.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"7"},"PeriodicalIF":5.9,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10810875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139564494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple.","authors":"Runa Zhang, Si-Wei Li, Lijuan Liu, Jun Yang, Guofu Huang, Yi Sang","doi":"10.1038/s41389-023-00506-x","DOIUrl":"10.1038/s41389-023-00506-x","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"5"},"PeriodicalIF":6.2,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10781686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139417739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair","authors":"Yujia Huang, Ming Tang, Zhiyi Hu, Bailian Cai, Guofang Chen, Lijun Jiang, Yan Xia, Pujun Guan, Xiaoqi Li, Zhiyong Mao, Xiaoping Wan, Wen Lu","doi":"10.1038/s41389-023-00503-0","DOIUrl":"https://doi.org/10.1038/s41389-023-00503-0","url":null,"abstract":"<p>Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"34 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139397205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription","authors":"Xuanmao Jiao, Gabriele Di Sante, Mathew C. Casimiro, Agnes Tantos, Anthony W. Ashton, Zhiping Li, Yen Quach, Dharmendra Bhargava, Agnese Di Rocco, Claudia Pupo, Marco Crosariol, Tamas Lazar, Peter Tompa, Chenguang Wang, Zuoren Yu, Zhao Zhang, Kawthar Aldaaysi, Ratna Vadlamudi, Monica Mann, Emmanuel Skordalakes, Andrew Kossenkov, Yanming Du, Richard G. Pestell","doi":"10.1038/s41389-023-00502-1","DOIUrl":"https://doi.org/10.1038/s41389-023-00502-1","url":null,"abstract":"<p>The essential G₁-cyclin, <i>CCND1</i>, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G₁-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2B^S14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2B^S14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"6 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139397088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic analysis identifies B-lymphocyte kinase as a therapeutic target for desmoplastic small round cell tumor cancer stem cell-like cells.","authors":"Justin W Magrath, Dane A Flinchum, Alifiani B Hartono, Shruthi Sanjitha Sampath, Tina M O'Grady, Melody Baddoo, Liang Haoyang, Xiaojiang Xu, Erik K Flemington, Sean B Lee","doi":"10.1038/s41389-023-00504-z","DOIUrl":"10.1038/s41389-023-00504-z","url":null,"abstract":"<p><p>Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15-25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state, which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks, including 4444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression, including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1-regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties, including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance, making its inhibition a promising target for future combination therapy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"2"},"PeriodicalIF":6.2,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10767073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell competition and cancer from Drosophila to mammals.","authors":"Bojie Cong, Ross L Cagan","doi":"10.1038/s41389-023-00505-y","DOIUrl":"10.1038/s41389-023-00505-y","url":null,"abstract":"<p><p>Throughout an individual's life, somatic cells acquire cancer-associated mutations. A fraction of these mutations trigger tumour formation, a phenomenon partly driven by the interplay of mutant and wild-type cell clones competing for dominance; conversely, other mutations function against tumour initiation. This mechanism of 'cell competition', can shift clone dynamics by evaluating the relative status of clonal populations, promoting 'winners' and eliminating 'losers'. This review examines the role of cell competition in the context of tumorigenesis, tumour progression and therapeutic intervention.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"1"},"PeriodicalIF":6.2,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10764339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed cell death 11 modulates but not entirely relies on p53-HDM2 loop to facilitate G2/M transition in colorectal cancer cells","authors":"Li Ding, Yujie Xu, Lin Xu, Chenhong Zhao, Zhiping Zhang, Jie Zhang, Kai Liao, Yuerou Chen, Jingwen Li, Xinyu Mei, Xinyue Zhang","doi":"10.1038/s41389-023-00501-2","DOIUrl":"https://doi.org/10.1038/s41389-023-00501-2","url":null,"abstract":"<p>We previously described a nucleolar protein RSL1D1 but distributed throughout the nucleus in HCT116 colorectal cancer (CRC) cells to facilitate G1/S transition by inhibiting p53 signaling. Here, we found another nucleolar protein, programmed cell death 11 (PDCD11), also with an “Extra-nucleolar” localization in CRC cells but to regulate G2/M checkpoint. This protein directly interacts with p53 and HDM2 in the nucleoplasm, thereby recruiting p53 to HDM2 for ubiquitination and degradation. The ensuing downregulation of p53 increases the CDK1 level to help the cells pass G2/M checkpoint. Upon DNA damage stress, PDCD11 gains the power to upregulate CDK1 independently of p53. Beyond these, PDCD11 also upregulates CDC25C in a p53-independent manner to dephosphorylate CDK1 to facilitate G2/M transition. Downregulation of PDCD11 greatly reduced cancer cell growth in vitro and in vivo, additionally sensitized cells to DNA damage signals, highlighting that PDCD11 is a crucial driving factor of CRC and a potential target for cancer treatment.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"195 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138557084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying a locus in super-enhancer and its resident NFE2L1/MAFG as transcriptional factors that drive PD-L1 expression and immune evasion.","authors":"Conglin Shi, Liuting Chen, Hui Pi, Henglu Cui, Chenyang Fan, Fangzheng Tan, Xuanhao Qu, Rong Sun, Fengbo Zhao, Yihua Song, Yuanyuan Wu, Miaomiao Chen, Wenkai Ni, Lishuai Qu, Renfang Mao, Yihui Fan","doi":"10.1038/s41389-023-00500-3","DOIUrl":"10.1038/s41389-023-00500-3","url":null,"abstract":"<p><p>Although the transcriptional regulation of the programmed death ligand 1 (PD-L1) promoter has been extensively studied, the transcription factor residing in the PD-L1 super-enhancer has not been comprehensively explored. Through saturated CRISPR-Cas9 screening of the core region of the PD-L1 super-enhancer, we have identified a crucial genetic locus, referred to as locus 22, which is essential for PD-L1 expression. Locus 22 is a potential binding site for NFE2:MAF transcription factors. Although genetic silencing of NRF2 (NFE2L2) did not result in a reduction of PD-L1 expression, further analysis reveals that MAFG and NFE2L1 (NRF1) play a critical role in the expression of PD-L1. Importantly, lipopolysaccharides (LPS) as the major component of intratumoral bacteria could greatly induce PD-L1 expression, which is dependent on the PD-L1 super-enhancer, locus 22, and NFE2L1/MAFG. Mechanistically, genetic modification of locus 22 and silencing of MAFG greatly reduce BRD4 binding and loop formation but have minimal effects on H3K27Ac modification. Unlike control cells, cells with genetic modification of locus 22 and silencing of NFE2L1/MAFG failed to escape T cell-mediated killing. In breast cancer, the expression of MAFG is positively correlated with the expression of PD-L1. Taken together, our findings demonstrate the critical role of locus 22 and its associated transcription factor NFE2L1/MAFG in super-enhancer- and LPS-induced PD-L1 expression. Our findings provide new insight into understanding the regulation of PD-L1 transcription and intratumoral bacteria-mediated immune evasion.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"56"},"PeriodicalIF":6.2,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10662283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NF-κB signaling activation and roles in thyroid cancers: implication of MAP3K14/NIK.","authors":"Françoise Cormier, Selma Housni, Florent Dumont, Mélodie Villard, Béatrix Cochand-Priollet, Françoise Mercier-Nomé, Karine Perlemoine, Jérôme Bertherat, Lionel Groussin","doi":"10.1038/s41389-023-00496-w","DOIUrl":"10.1038/s41389-023-00496-w","url":null,"abstract":"<p><p>Among follicular-derived thyroid cancers (TC), those with aggressive behavior and resistance to current treatments display poor prognosis. NF-κB signaling pathways are involved in tumor progression of various cancers. Here, we finely characterize the NF-κB pathways and their involvement in TC. By using immunoblot and gel shift assays, we demonstrated that both classical and alternative NF-κB pathways are activated in ten TC-derived cell lines, leading to activated RelA/p50 and RelB/p50 NF-κB dimers. By analyzing the RNAseq data of the large papillary thyroid carcinoma (PTC) cohort from The Cancer Genome Atlas (TCGA) project, we identified a tumor progression-related NF-κB signature in BRAF^V600E mutated-PTCs. That corroborated with the role of RelA and RelB in cell migration and invasion processes that we demonstrated specifically in BRAF^V600E mutated-cell lines, together with their role in the control of expression of genes implicated in invasiveness (MMP1, PLAU, LCN2 and LGALS3). We also identified NF-κB-inducing kinase (NIK) as a novel actor of the constitutive activation of the NF-κB pathways in TC-derived cell lines. Finally, its implication in invasiveness and its overexpression in PTC samples make NIK a potential therapeutic target for advanced TC treatment.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"12 1","pages":"55"},"PeriodicalIF":6.2,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10654696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136398535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}