Cell Death and Differentiation最新文献_第7页

Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC−/− Mice DNA修复缺陷FANCC c.67delG突变体和FANCC−/−小鼠的不同发育结果

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-17 DOI: 10.1038/s41418-025-01461-3

Swarna Beesetti, Cliff Guy, Shyam Sirasanagandla, Mao Yang, Rhea Jr Sumpter, Heather Sheppard, Stephane Pelletier, Marcin W. Wlodarski, Douglas R. Green

{"title":"Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC−/− Mice","authors":"Swarna Beesetti, Cliff Guy, Shyam Sirasanagandla, Mao Yang, Rhea Jr Sumpter, Heather Sheppard, Stephane Pelletier, Marcin W. Wlodarski, Douglas R. Green","doi":"10.1038/s41418-025-01461-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01461-3","url":null,"abstract":"Fanconi Anemia (FA) is an autosomal recessive disorder characterized by diverse clinical manifestations such as aplastic anemia, cancer predisposition, and developmental defects including hypogonadism, microcephaly, organ dysfunction, infertility, hyperpigmentation, microphthalmia, and skeletal defects. In addition to the well-described defects in DNA repair, mitochondrial dysfunction due to defects in mitochondrial autophagy (mitophagy) is also associated with FA, although its contribution to FA phenotypes is unknown. This study focused on the FANCC gene, which, alongside other FA genes, is integral to DNA repair and mitochondrial quality control. In the present study, we created a FANCC mutant mouse model, based on a human mutation (FANCC c.67delG) that is defective in DNA repair but proficient in mitophagy. We found that the FANCC c.67delG mutant mouse model recapitulates some phenotypes observed in FA patients, such as cellular hypersensitivity to DNA cross-linking agents and hematopoietic defects. In contrast, FA phenotypes such as microphthalmia, hypogonadism, and infertility, present in FANCC-deficient mice, were absent in the FANCC c.67delG mice, suggesting that the N-terminal 55 amino acids of FANCC are dispensable for these developmental processes. Furthermore, the FANCC c.67delG mutation preserved mitophagy, and unlike the FANCC null mutation, did not lead to the accumulation of damaged mitochondria in cells or tissues. This study highlights the multifaceted nature of the FANCC protein, with distinct domains responsible for DNA repair and mitophagy. Our results suggest that developmental defects in FA may not solely stem from DNA repair deficiencies but could also involve other functions, such as mitochondrial quality control.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"64 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434996","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

STING directly interacts with PAR to promote apoptosis upon acute ionizing radiation-mediated DNA damage STING直接与PAR相互作用，促进急性电离辐射介导的DNA损伤后的细胞凋亡

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-12 DOI: 10.1038/s41418-025-01457-z

Yirong Sun, Saba R. Aliyari, Kislay Parvatiyar, Lulan Wang, Anjie Zhen, Wei Sun, Xiaobo Han, Adele Zhang, Ethan Kato, Helen Shi, Elena De Schutter, William H. McBride, Samuel W. French, Genhong Cheng

{"title":"STING directly interacts with PAR to promote apoptosis upon acute ionizing radiation-mediated DNA damage","authors":"Yirong Sun, Saba R. Aliyari, Kislay Parvatiyar, Lulan Wang, Anjie Zhen, Wei Sun, Xiaobo Han, Adele Zhang, Ethan Kato, Helen Shi, Elena De Schutter, William H. McBride, Samuel W. French, Genhong Cheng","doi":"10.1038/s41418-025-01457-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01457-z","url":null,"abstract":"Acute ionizing radiation (IR) causes severe DNA damage, leading to cell cycle arrest, cell death, and activation of the innate immune system. The role and signaling pathway of stimulator of interferon genes (STING) in IR-induced tissue damage and cell death are not well understood. This study revealed that STING is crucial for promoting apoptosis in response to DNA damage caused by acute IR both in vitro and in vivo. STING binds to poly (ADP‒ribose) (PAR) produced by activated poly (ADP‒ribose) polymerase-1 (PARP1) upon IR. Compared with that in WT cells, apoptosis was suppressed in Stinggt-/gt- cells. Excessive PAR production by PARP1 due to DNA damage enhances STING phosphorylation, and inhibiting PARP1 reduces cell apoptosis after IR. In vivo, IR-induced crypt cell death was significantly lower in Stinggt-/gt- mice or with low-dose PARP1 inhibitor, PJ34, resulting in substantial resistance to abdominal irradiation. STING deficiency or inhibition of PARP1 function can reduce the expression of the proapoptotic gene PUMA, decrease the localization of Bax on the mitochondrial membrane, and thus reduce cell apoptosis. Our findings highlight crucial roles for STING and PAR in the IR-mediated induction of apoptosis, which may have therapeutic implications for controlling radiation-induced apoptosis or acute radiation symptoms.<figure>STING responds to acute ionizing radiation-mediated DNA damage by directly binding to poly (ADP-ribose) (PAR) produced by activated poly (ADP-ribose) polymerase-1 (PARP1), and mainly induces cell apoptosis through Puma-Bax interaction. STING deficiency or reduced production of PAR protected mice against Acute Radiation Syndrome.</figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401328","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

EZH2 suppresses IR-induced ferroptosis by forming a co-repressor complex with HIF-1α to inhibit ACSL4: Targeting EZH2 enhances radiosensitivity in KDM6A-deficient esophageal squamous carcinoma EZH2通过与HIF-1α形成共抑制复合物抑制ACSL4，抑制ir诱导的铁凋亡：靶向EZH2增强kdm6a缺陷食管鳞状癌的放射敏感性

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-07 DOI: 10.1038/s41418-025-01451-5

Guizhen Pan, Yeye Xia, Mengyu Hao, Jiahao Guan, Qianqian Zhu, Tianqi Zha, Lei Sheng, Zhenfeng Zhao, Huaguang Pan, Weiyang Fang, Xiaoyong Xu, Xiangcun Chen, Shuguang Zhou, Zhuting Tong

{"title":"EZH2 suppresses IR-induced ferroptosis by forming a co-repressor complex with HIF-1α to inhibit ACSL4: Targeting EZH2 enhances radiosensitivity in KDM6A-deficient esophageal squamous carcinoma","authors":"Guizhen Pan, Yeye Xia, Mengyu Hao, Jiahao Guan, Qianqian Zhu, Tianqi Zha, Lei Sheng, Zhenfeng Zhao, Huaguang Pan, Weiyang Fang, Xiaoyong Xu, Xiangcun Chen, Shuguang Zhou, Zhuting Tong","doi":"10.1038/s41418-025-01451-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01451-5","url":null,"abstract":"The mutation status of the lysine demethylase 6 A (KDM6A), a gene antagonist to Enhancer of zeste homolog 2 (EZH2), is closely related to the therapeutic efficacy of EZH2 inhibitors in several malignancies. However, the mutational landscape of KDM6A and the therapeutic targetability of EZH2 inhibitors in esophageal squamous carcinoma (ESCC) remain unreported. Here, we found that approximately 9.18% (9/98) of our study ESCC tissues had KDM6A mutations of which 7 cases resulted in a complete loss of expression and consequent loss of demethylase function. We found that KDM6A-deficient ESCC cells exhibited increased sensitivity to EZH2 inhibitor, and the radiosensitizing activity of EZH2 inhibitor was evident in KDM6A-dficient ESCC cells. Further transcriptome analysis revealed that ferroptosis is implicated in the radiosensitizing effect exerted by EZH2 inhibition on KDM6A-deficient ESCC cells. The following Chromatin Immunoprecipitation (ChIP), co-immunoprecipitation, and luciferase reporter assays demonstrated that in KDM6A-deficient ESCC cells, (1) Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) is the target gene for EZH2 to regulate ferroptosis; (2) The IR-induced hypoxia inducible factor 1 subunit alpha (HIF-1α) is a predominant mediator of EZH2 to repress ACSL4; (3) the HRE7-8 regions of the ACSL4 promoter are required for the repressive function of EZH2 on ACSL4; (4) EZH2 regulates ACSL4 by forming a co-repressive complex with HIF-1α. Our study provides preclinical evidence supporting that EZH2 inhibitors may confer therapeutic benefit in KDM6A-deficient ESCC patients.<figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367249","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

Correction: SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy. 更正：抑制SENP3可抑制肝癌进展，提高抗pd -1免疫治疗的疗效。

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-06 DOI: 10.1038/s41418-025-01455-1

Peng Wang, Jiannan Qiu, Yuan Fang, Songmao Li, Kua Liu, Yin Cao, Guang Zhang, Zhongxia Wang, Xiaosong Gu, Junhua Wu, Chunping Jiang

引用次数: 0

Inhibition of ferroptosis counteracts the advanced maternal age-induced oocyte deterioration 抑制铁下垂可抵消高龄产妇引起的卵母细胞退化

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-06 DOI: 10.1038/s41418-025-01456-0

Wenjun Zeng, Feixue Wang, Zhaokang Cui, Yu Zhang, Yu Li, Na Li, Zipeng Mao, Hanwen Zhang, Yiting Liu, Yilong Miao, Shaochen Sun, Yafei Cai, Bo Xiong

{"title":"Inhibition of ferroptosis counteracts the advanced maternal age-induced oocyte deterioration","authors":"Wenjun Zeng, Feixue Wang, Zhaokang Cui, Yu Zhang, Yu Li, Na Li, Zipeng Mao, Hanwen Zhang, Yiting Liu, Yilong Miao, Shaochen Sun, Yafei Cai, Bo Xiong","doi":"10.1038/s41418-025-01456-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01456-0","url":null,"abstract":"Ferroptosis, a recently discovered form of programmed cell death triggered by the excessive accumulation of iron-dependent lipid peroxidation products, plays a critical role in the development of various diseases. However, whether it is involved in the age-related decline in oocyte quality remains unexplored. Here, we took advantage of nano-proteomics to uncover that reduced ferritin heavy chain (Fth1) level is a major cause leading to the occurrence of ferroptosis in aged oocytes. Specifically, induction of ferroptosis in young oocytes by its activators RSL3 and FAC, or knockdown of Fth1 all phenocopied the meiotic defects observed in aged oocytes, including failed oocyte meiotic maturation, aberrant cytoskeleton dynamics, as well as impaired mitochondrial function. Transcriptome analysis showed that knockdown of Fth1 affected meiosis-related and aging-related pathways in oocytes. Conversely, inhibition of ferroptosis by its inhibitors or expression of Fth1 improved the quality of aged oocytes. We also validated the effects of ferroptosis on the porcine oocyte quality in vitro. Altogether, we demonstrate the contribution of ferroptosis to the age-induced oocyte defects and evidence that inhibition of ferroptosis might be a feasible strategy to ameliorate the reproductive outcomes of female animals at an advanced age.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192101","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

Protein kinase A regulates ferroptosis by controlling GPX4 m6A modification through phosphorylation of ALKBH5 蛋白激酶A通过磷酸化ALKBH5调控GPX4 m6A修饰，从而调控铁下垂

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-03 DOI: 10.1038/s41418-025-01453-3

Xiaocheng Zhao, Yanxi Sun, Juan Zou, Yanxia Wu, Minyi Huang, Huimin Kong, Guangda Liu, Holger Gerhardt, Wei Gu, Yunjiao Zhang, Min Shang, Xingwu Wang

引用次数: 0

Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors 破译MCL-1/BAK相互作用的分子特异性及其对设计强效MCL-1抑制剂的意义

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-02-03 DOI: 10.1038/s41418-025-01454-2

Hudie Wei, Haolan Wang, Shuang Xiang, Jiaqi Wang, Lingzhi Qu, Xiaojuan Chen, Ming Guo, Xiaoyun Lu, Yongheng Chen

{"title":"Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors","authors":"Hudie Wei, Haolan Wang, Shuang Xiang, Jiaqi Wang, Lingzhi Qu, Xiaojuan Chen, Ming Guo, Xiaoyun Lu, Yongheng Chen","doi":"10.1038/s41418-025-01454-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01454-2","url":null,"abstract":"The intricate interplay among BCL-2 family proteins governs mitochondrial apoptosis, with the anti-apoptotic protein MCL-1 primarily exerting its function by sequestering the pore-forming effector BAK. Understanding the MCL-1/BAK complex is pivotal for the sensitivity of cancer cells to BH3 mimetics, yet the precise molecular mechanism underlying their interaction remains elusive. Herein, we demonstrate that a canonical BH3 peptide from BAK inadequately binds to MCL-1 proteins, whereas an extended BAK-BH3 peptide with five C-terminal residues exhibits a remarkable 65-fold increase in affinity. By elucidating the complex structures of MCL-1 bound to these two BAK-BH3 peptides at 2.08 Å and 1.98 Å resolutions, we uncover their distinct binding specificities. Notably, MCL-1 engages in critical hydrophobic interactions with the extended BAK-BH3 peptide, particularly at an additional p5 sub-pocket, featuring a π-π stacking interaction between MCL-1 Phe319 and BAK Tyr89. Mutations within this p5 sub-pocket substantially disrupt the MCL-1/BAK protein-protein interaction. Furthermore, the p5 sub-pocket of MCL-1 significantly influences the efficacy of MCL-1 inhibitors. Overall, our findings elucidate the molecular specificity underlying MCL-1 binding to BAK and underscore the significance of the p5 hydrophobic sub-pocket in their high-affinity interaction, thus providing novel insights for the development of BH3 mimetics targeting the MCL-1/BAK interaction as potential therapeutics for cancer treatment.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"130 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077620","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

Redox regulation of TRIM28 facilitates neuronal ferroptosis by promoting SUMOylation and inhibiting OPTN-selective autophagic degradation of ACSL4 TRIM28的氧化还原调节通过促进SUMOylation和抑制optn选择性ACSL4的自噬降解来促进神经元铁凋亡

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-01-28 DOI: 10.1038/s41418-025-01452-4

Wei Liu, Yufeng Zhu, Wu Ye, Junjun Xiong, Haofan Wang, Yu Gao, Shixue Huang, Yinuo Zhang, Xin Zhou, Xuhui Zhou, Xuhui Ge, Weihua Cai, Xingdong Zheng

{"title":"Redox regulation of TRIM28 facilitates neuronal ferroptosis by promoting SUMOylation and inhibiting OPTN-selective autophagic degradation of ACSL4","authors":"Wei Liu, Yufeng Zhu, Wu Ye, Junjun Xiong, Haofan Wang, Yu Gao, Shixue Huang, Yinuo Zhang, Xin Zhou, Xuhui Zhou, Xuhui Ge, Weihua Cai, Xingdong Zheng","doi":"10.1038/s41418-025-01452-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01452-4","url":null,"abstract":"Ferroptosis is one of the cell death programs occurring after spinal cord injury (SCI) and is driven by iron-dependent phospholipid peroxidation. However, little is known about its underlying regulation mechanism. The present study demonstrated that lipid peroxidation was promoted in patients with SCI. Neurons affected by ferroptosis following SCI had a high expression of ferroptotic protein ACSL4. The E3 SUMOylase TRIM28 promoted neuronal ferroptosis by enhancing ACSL4 expression. Genetic deletion of Trim28 significantly attenuated neuronal ferroptosis and improved mouse hindlimb motor function following SCI. In contrast, mice with Trim28 overexpression demonstrated poor neurological function after SCI, which was attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM28 bound to ACSL4, promoted SUMO3 modification at lysine (K) 532, and inhibited K63-linked ACSL4 ubiquitination, thereby suppressing OPTN-dependent autophagic degradation. Additionally, SENP3 was identified as the deSUMOylation enzyme that can reverse this process and compete with TRIM28, which was transcriptionally upregulated due to excessive oxidative stress. These data unveiled a mechanism by which TRIM28-mediated SUMOylation regulated neuronal ACSL4 levels and ferroptosis, identified interactions and correlations involved in ACSL4 SUMOylation, ubiquitination, and autophagic degradation, and discovered a positive feedback loop where oxidative stress transcriptionally upregulated Trim28, and conversely TRIM28 promoted ferroptosis and oxidative stress. Notably, screening of the FDA-approved drug library revealed that pharmacological TRIM28/ACSL4 axis interventions with Rutin hydrate inhibited neuronal ferroptosis and improved hindlimb motor function in mice after SCI, thus providing a promising therapeutic strategy for its treatment.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"89 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049941","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

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-01-28 DOI: 10.1038/s41418-025-01448-0

Lu Wan, Fumin Yang, Anqi Yin, Yong Luo, Yi Liu, Fei Liu, Jian-Zhi Wang, Rong Liu, Xiaochuan Wang

{"title":"Age-related p53 SUMOylation accelerates senescence and tau pathology in Alzheimer’s disease","authors":"Lu Wan, Fumin Yang, Anqi Yin, Yong Luo, Yi Liu, Fei Liu, Jian-Zhi Wang, Rong Liu, Xiaochuan Wang","doi":"10.1038/s41418-025-01448-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01448-0","url":null,"abstract":"Aging is a major risk factor for Alzheimer’s disease (AD). With the prevalence of AD increased, a mechanistic linkage between aging and the pathogenesis of AD needs to be further addressed. Here, we report that a small ubiquitin-related modifier (SUMO) modification of p53 is implicated in the process which remarkably increased in AD patient’s brain. Mechanistically, SUMOylation of p53 at K386 residue causes the dissociation of SET/p53 complex, thus releasing SET into the cytoplasm, SET further interacts with cytoplasmic PP2A and inhibits its activity, resulting in tau hyperphosphorylation in neurons. In addition, SUMOylation of p53 promotes the p53 Ser15 phosphorylation that mediates neuronal senescence. Notably, p53 SUMOylation contributes to synaptic damage and cognitive defects in AD model mice. We also demonstrate that the SUMOylation inhibiter, Ginkgolic acid, recovering several senescent phenotypes drove by p53 SUMOylation in primary neurons. These findings suggest a previously undiscovered etiopathogenic relationship between aging and AD that is linked to p53 SUMOylation and the potential of SUMOylated p53-based therapeutics for neurodegeneration such as Alzheimer’s disease.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"20 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049943","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

YAP/TEAD4/SP1-induced VISTA expression as a tumor cell-intrinsic mechanism of immunosuppression in colorectal cancer YAP/TEAD4/ sp1诱导的VISTA表达作为结直肠癌免疫抑制的肿瘤细胞内在机制

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2025-01-28 DOI: 10.1038/s41418-025-01446-2

Zhehui Zhu, Rui Ding, Wei Yu, Yun Liu, Zhaocai Zhou, Chen-Ying Liu

{"title":"YAP/TEAD4/SP1-induced VISTA expression as a tumor cell-intrinsic mechanism of immunosuppression in colorectal cancer","authors":"Zhehui Zhu, Rui Ding, Wei Yu, Yun Liu, Zhaocai Zhou, Chen-Ying Liu","doi":"10.1038/s41418-025-01446-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01446-2","url":null,"abstract":"Hyperactivation of the YAP/TEAD transcriptional complex in cancers facilitates the development of an immunosuppressive tumor microenvironment. Herein, we observed that the transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci in colorectal cancer (CRC). In response to serum stimulation, PKCζ (protein kinase C ζ) was found to phosphorylate SP1 and enhance its interaction with TEAD4. As a result, SP1 enhanced the transcriptional activity of YAP/TEAD and coregulated the expression of a group of YAP/TEAD target genes. The immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) was identified as a direct target of the SP1-YAP/TEAD4 complex and found to be widely expressed in CRC cells. Importantly, YAP-induced VISTA upregulation in human CRC cells was found to strongly suppress the antitumor function of CD8+ T cells. Consistently, elevated VISTA expression was found to be correlated with hyperactivation of the SP1-YAP/TEAD axis and associated with poor prognosis of CRC patients. In addition, we found by serendipity that enzymatic deglycosylation significantly improved the anti-VISTA antibody signal intensity, resulting in more accurate detection of VISTA in clinical tumor samples. Overall, our study identified SP1 as a positive modulator of YAP/TEAD for the transcriptional regulation of VISTA and developed a protein deglycosylation strategy to better detect VISTA expression in clinical samples. These findings revealed a new tumor cell-intrinsic mechanism of YAP/TAZ-mediated cancer immune evasion.<figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"25 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049944","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