Nature Cell Biology最新文献_第6页

An EZH2–SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis EZH2-SREBP2轴促进胆固醇生物合成，并代表肿瘤发生中的非典型易损性

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-14 DOI: 10.1038/s41556-026-02048-x

Arum Kim, Bo Pan, Xufen Yu, Xing Gao, Nelli Khudaverdyan, Fatemeh Taherian, Chenxi Xu, Haiqing Zhong, Yan Xiong, H. Ümit Kaniskan, Masoud Vedadi, Jikui Song, Jian Jin, Ling Cai, Gang Greg Wang

{"title":"An EZH2–SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis","authors":"Arum Kim, Bo Pan, Xufen Yu, Xing Gao, Nelli Khudaverdyan, Fatemeh Taherian, Chenxi Xu, Haiqing Zhong, Yan Xiong, H. Ümit Kaniskan, Masoud Vedadi, Jikui Song, Jian Jin, Ling Cai, Gang Greg Wang","doi":"10.1038/s41556-026-02048-x","DOIUrl":"10.1038/s41556-026-02048-x","url":null,"abstract":"Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in cancer, correlating with adverse clinical outcomes. However, how EZH2 overexpression supports tumorigenicity is not fully elucidated. Here we identify a previously unexplored tumour-promoting axis involving EZH2–SREBP2 association. EZH2 and SREBP2, a master regulator of lipid metabolism, cooperate to drive high expression of mevalonate pathway genes, enhancing cholesterol biosynthesis and sustaining tumour growth. Transcriptional activation domains of EZH2 and SREBP2 bind p300 directly, mediating proto-oncogene activation. Furthermore, we employed proteolysis targeting chimeras (PROTACs) to target this non-canonical EZH2 function. Independent EZH2-targeting PROTACs degrade both EZH2 and SREBP2, downregulating SREBP2-associated gene-expression programmes and inhibiting tumour growth. Collectively, this study unveils an EZH2–SREBP2 regulatory axis that promotes cholesterol biosynthesis and fuels tumorigenesis, shifting the current paradigm of EZH2’s oncogenic functions. Kim et al. demonstrate a non-canonical function for EZH2 in modulating cholesterol metabolism and tumour development by interacting with SREBP2, which may be targeted by PROTACs to disrupt its oncogenic activity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 10","pages":"2138-2154"},"PeriodicalIF":22.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A chromatin remodeller silences SINE retrotransposons 一种染色质重塑剂使sin反转录转座子沉默

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-10 DOI: 10.1038/s41556-026-02051-2

Sabrya Carim

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Mega-enhancers compartmentalize transcriptionally active long genes in the brain 巨型增强子将大脑中具有转录活性的长基因分隔开来。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-10 DOI: 10.1038/s41556-026-02043-2

Ziyu Zhao, Omar A. Payán Parra, Shin-ichiro Fujita, Francesco Musella, Nicolas J. Scrutton Alvarado, Frank Alber, Yue Yang, Tomoko Yamada

{"title":"Mega-enhancers compartmentalize transcriptionally active long genes in the brain","authors":"Ziyu Zhao, Omar A. Payán Parra, Shin-ichiro Fujita, Francesco Musella, Nicolas J. Scrutton Alvarado, Frank Alber, Yue Yang, Tomoko Yamada","doi":"10.1038/s41556-026-02043-2","DOIUrl":"10.1038/s41556-026-02043-2","url":null,"abstract":"Exceptionally long genes and cis-regulatory enhancers are selectively activated in mammalian brain neurons, and these loci are mutation hotspots in neurological disorders. However, the organization of these large genomic elements at the level of chromosome folding, beyond local enhancer–promoter interactions, remains poorly understood. Here we report the discovery of a genomic subcompartment in the mouse cerebellum formed by near-megabase-long enhancers and their associated long genes encoding synaptic or signalling proteins. Genomic regions within this subcompartment are enriched in the outer half of the nucleus, whereas other transcriptionally active structures are enriched in the nuclear interior. Using an in vivo CRISPR genetic mini screen, we uncover a specific role for the transcription factor Etv1 in coupling the compartmentalization of neuronal long genes with their expression. Together, our study defines mechanisms that organize transcriptionally active genes across chromosomes in the mammalian brain. Zhao et al. describe an enhancer-dense nuclear microenvironment in the cerebellum that includes long neuronal genes and mega-enhancers. This microenvironment partly depends on the transcription factor Etv1 and is dynamic during neuronal maturation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 9","pages":"1913-1926"},"PeriodicalIF":22.7,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: HERD-1 mediates multiphase condensate immiscibility to regulate small RNA-driven transgenerational epigenetic inheritance 作者更正：HERD-1介导多相凝析不混溶调节小rna驱动的跨代表观遗传。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-10 DOI: 10.1038/s41556-026-02060-1

Changfeng Zhao, Shiyu Cai, Ruona Shi, Xinru Li, Boyuan Deng, Ruofei Li, Shuhan Yang, Jing Huang, Yonglin Liang, Pu Lu, Zhongping Yuan, Haoxiang Jia, Zongjin Jiang, Xiaofei Zhang, Scott Kennedy, Gang Wan

引用次数: 0

Early human crosstalk 早期人类相声

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-10 DOI: 10.1038/s41556-026-02049-w

Stylianos Lefkopoulos

引用次数: 0

Advanced imaging of membrane contact sites 先进的膜接触部位成像

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-07 DOI: 10.1038/s41556-026-02003-w

Riccardo Filadi, Ambra Bertocco, Michela Rossini, Paola Pizzo

引用次数: 0

Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia 靶向致癌性FLT3通过硒代半胱氨酸重编码在急性髓性白血病中揭示铁下垂易损性

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-07 DOI: 10.1038/s41556-026-02016-5

Minhua Li, Yudan Zhu, Yuki Kageyama, Ken Furudate, Ayumi Kitano, Taotao Tan, Mengdie Feng, Jing Zhou, Tao Wang, Robert J. Taylor, Alexandra M. Stevens, Md. Abul Hassan Samee, Jeffrey A. Magee, Koichi Takahashi, Daisuke Nakada

{"title":"Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia","authors":"Minhua Li, Yudan Zhu, Yuki Kageyama, Ken Furudate, Ayumi Kitano, Taotao Tan, Mengdie Feng, Jing Zhou, Tao Wang, Robert J. Taylor, Alexandra M. Stevens, Md. Abul Hassan Samee, Jeffrey A. Magee, Koichi Takahashi, Daisuke Nakada","doi":"10.1038/s41556-026-02016-5","DOIUrl":"10.1038/s41556-026-02016-5","url":null,"abstract":"Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis. Li et al. report that FLT3 inhibition impairs selenoprotein translation and induces ferroptosis to suppress FLT3-mutant leukaemia. This can be counteracted by dietary vitamin E, which may disrupt the efficacy of tyrosine kinase inhibitors in treatment of acute myeloid leukaemia.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1715-1727"},"PeriodicalIF":22.7,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02016-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148693562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation 线粒体酶OGDH通过许可mettl3调节的NRF2翻译来防御二硫磷酸症。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-07 DOI: 10.1038/s41556-026-02042-3

Xiao-yan Chen, Ke-jun Xu, Jia-xin Zhou, Liu-zheng Wu, De-yi Feng, Yun-feng Guan, Heng-hui Li, Guang-xi Yang, Yu Qian, Meng-hao Mi, Sheng-fu Wu, Zhi-yuan Zhang, Qi-tao Chen, Bo Zhou, Hang-zi Chen

{"title":"The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation","authors":"Xiao-yan Chen, Ke-jun Xu, Jia-xin Zhou, Liu-zheng Wu, De-yi Feng, Yun-feng Guan, Heng-hui Li, Guang-xi Yang, Yu Qian, Meng-hao Mi, Sheng-fu Wu, Zhi-yuan Zhang, Qi-tao Chen, Bo Zhou, Hang-zi Chen","doi":"10.1038/s41556-026-02042-3","DOIUrl":"10.1038/s41556-026-02042-3","url":null,"abstract":"Disulfidptosis is a form of regulated cell death triggered by disulfide stress resulting from glucose starvation. The capacity to evade disulfidptosis is crucial for tumour cells to withstand glucose-limited environments. Here we demonstrate that OGDH, a rate-limiting enzyme in citric acid cycle, is critical for conferring resistance to disulfidptosis. High expression of HSPA9 in melanoma protects OGDH from glucose deprivation-induced oxidative inactivation, thereby ensuring OGDH-generated succinyl-CoA for METTL3 succinylation. Succinylated METTL3 recognizes m6A modification on NRF2 mRNA to license NRF2 translation, TrxR1 expression and subsequent evasion of disulfidptosis. Combined suppression of HSPA9 and glucose uptake inhibits melanoma growth in mouse models. In patients with melanoma, expressions of HSPA9 and OGDH negatively correlate with the disulfidptosis signature and are associated with an unfavourable clinical prognosis. Therefore, our findings not only highlight the dependence of melanoma cells on the HSPA9–OGDH–METTL3–NRF2 axis for disulfidptosis evasion, but also propose a combined intervention strategy for melanoma therapy. Chen, Xu, Zhou, Wu et al. report that a citric acid cycle enzyme OGDH regulates METTL3 succinylation and its activation as an m6A reader, thereby modulating NRF2 translation, disulfidptosis evasion and tumour growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 9","pages":"1814-1829"},"PeriodicalIF":22.7,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PGAM1 rheostat in glycolysis and autophagy 糖酵解和自噬中的PGAM1变阻器。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-07 DOI: 10.1038/s41556-026-02033-4

Kay F. Macleod

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Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk 癌前血细胞会使骨髓过早老化，从而增加患癌风险。

IF 22.7 1区生物学

Nature Cell Biology Pub Date : 2026-08-06 DOI: 10.1038/s41556-026-02032-5

引用次数: 0