Min Liu, Yuanyuan Li, Zhilin Deng, Ke Zhang, Shuying Huang, Jiamin Xia, Yi Feng, Yundan Liang, Chengfu Sun, Xindong Liu, Shurong Li, Bingyin Su, Yong Dong, Sizhou Huang
{"title":"Mcm5 mutation leads to silencing of Stat1-bcl2 which accelerating apoptosis of immature T lymphocytes with DNA damage.","authors":"Min Liu, Yuanyuan Li, Zhilin Deng, Ke Zhang, Shuying Huang, Jiamin Xia, Yi Feng, Yundan Liang, Chengfu Sun, Xindong Liu, Shurong Li, Bingyin Su, Yong Dong, Sizhou Huang","doi":"10.1038/s41419-025-07392-8","DOIUrl":"10.1038/s41419-025-07392-8","url":null,"abstract":"<p><p>Mutation in genes involved in DNA replication continuously disrupt DNA replication and give rise to genomic instability, a critical driver of oncogenesis. To prevent leukemia, immature T lymphocytes with genomic instability often undergo rapid cell death during development. However, the mechanism by which immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic. Here we show that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death. Detailed analyses demonstrated that the immature T lymphocytes undergo rapid apoptosis via upregulation of tp53 and downregulation of bcl2 transcription in mcm5 mutants. Mechanistically, Mcm5 directly binds to Stat1a and facilitates its phosphorylation to enhance bcl2a expression under the conditions of DNA replication stress. However, in mcm5 mutants, the absence of the Mcm5-Stat1 complex decreases Stat1 phosphorylation and subsequent bcl2a transcription, accelerating apoptosis of immature T lymphocytes with genomic instability. Furthermore, our study shows that the role of Mcm5 in T-cell development is conserved in mice. In conclusion, our work identifies a role of Mcm5 in regulating T cell development via Stat1-Bcl2 cascade besides its role in DNA replication, providing a kind of mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"84"},"PeriodicalIF":8.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390186","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}
Yong Ji, Han Zhang, Fei-Long Gong, Jia-Long Liang, Sheng-Fei Wang, Yong-Hua Sang, Ming-Feng Zheng
{"title":"The expression and functional role of proline-rich 15 in non-small cell lung cancer.","authors":"Yong Ji, Han Zhang, Fei-Long Gong, Jia-Long Liang, Sheng-Fei Wang, Yong-Hua Sang, Ming-Feng Zheng","doi":"10.1038/s41419-025-07373-x","DOIUrl":"10.1038/s41419-025-07373-x","url":null,"abstract":"<p><p>Proline-rich 15 (PRR15) is a protein primarily known for its role in placental development. This study investigates the expression, functional significance, and underlying mechanisms of PRR15 in non-small cell lung cancer (NSCLC). Our findings demonstrate significantly elevated PRR15 expression in NSCLC tissues compared to normal lung parenchyma, with higher expression correlating with adverse clinical outcomes. Single-cell RNA sequencing confirmed PRR15 overexpression within the malignant tumor cell population. PRR15 expression was elevated in NSCLC tissues from locally treated patients and in a panel of primary and established NSCLC cells. PRR15 depletion using shRNA or CRISPR/Cas9-mediated knockout significantly suppressed proliferation and migration, while promoting apoptosis in various NSCLC cells. Conversely, ectopic PRR15 overexpression using a lentiviral construct enhanced cell proliferation and migration. Mechanistic investigations implicated PRR15 in the activation of the Akt-mTOR signaling pathway. Inhibition of PRR15 expression via shRNA or CRISPR/Cas9-mediated knockout resulted in decreased Akt and S6K phosphorylation, while PRR15 overexpression led to augmented Akt-S6K signaling in primary human NSCLC cells. In vivo studies using xenograft models further validated the oncogenic role of PRR15, demonstrating that PRR15 knockdown suppressed tumor growth and attenuated Akt-mTOR activation. These findings collectively highlight the potential of PRR15 as a novel oncogenic driver and therapeutic target in NSCLC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"83"},"PeriodicalIF":8.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390187","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}
Qin Qi, Rui Zhong, Yan Huang, Yong Tang, Xiao-Wen Zhang, Chang Liu, Chun-Fang Gao, Lin Zhou, Jian Yu, Lu-Yi Wu
{"title":"The RNA M5C methyltransferase NSUN2 promotes progression of hepatocellular carcinoma by enhancing PKM2-mediated glycolysis.","authors":"Qin Qi, Rui Zhong, Yan Huang, Yong Tang, Xiao-Wen Zhang, Chang Liu, Chun-Fang Gao, Lin Zhou, Jian Yu, Lu-Yi Wu","doi":"10.1038/s41419-025-07414-5","DOIUrl":"10.1038/s41419-025-07414-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in cell proliferation and metastasis and is upregulated in a variety of cancers. However, the biological function and regulatory mechanism of NSUN2-mediated m5C modification have not been well studied in HCC. Our results showed that NSUN2 is upregulated and associated with poor prognosis in HCC patients after hepatectomy. NSUN2 overexpression significantly promoted HCC growth and metastasis, whereas NSUN2 knockdown had the opposite effect. m5C RNA immunoprecipitation sequencing (m5C-RIP-Seq) revealed that m5C hypermethylation correlates with mRNA overexpression and that NSUN2-mediated m5C hypermethylation promotes metabolism in HCC patients. Mechanistically, our data revealed that PKM2, a terminal enzyme in the glycolytic pathway, is a downstream target of NSUN2-mediated m5C modification. Specifically, NSUN2 could stabilize PKM2 mRNA by increasing the m5C level of the m5C site C773 in the 3'-UTR of PKM2 mRNA. In addition, rescue assays revealed that NSUN2 promotes HCC glycolysis and progression by upregulating PKM2. In conclusion, this study revealed that NSUN2-mediated m5C modification promotes glycolysis and the progression of hepatocellular carcinoma by stabilizing PKM2 mRNA, and provides a potential prognostic factor and therapeutic target for HCC patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"82"},"PeriodicalIF":8.1,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381714","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}
Zhongdong Xie, Hanbin Lin, Yuecheng Wu, Yanan Yu, Xintong Liu, Yating Zheng, Xiaojie Wang, Jiashu Wu, Meifang Xu, Yuting Han, Qiongying Zhang, Yu Deng, Lin Lin, Yan Linzhu, Li Qingyun, Xinjian Lin, Ying Huang, Pan Chi
{"title":"USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer.","authors":"Zhongdong Xie, Hanbin Lin, Yuecheng Wu, Yanan Yu, Xintong Liu, Yating Zheng, Xiaojie Wang, Jiashu Wu, Meifang Xu, Yuting Han, Qiongying Zhang, Yu Deng, Lin Lin, Yan Linzhu, Li Qingyun, Xinjian Lin, Ying Huang, Pan Chi","doi":"10.1038/s41419-025-07424-3","DOIUrl":"10.1038/s41419-025-07424-3","url":null,"abstract":"<p><p>Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to identify potential genes associated with the autophagy panel and assess their prognostic significance, biological roles, and mechanisms in CRC metastasis. Among the candidates, CENPF emerged as the top gene in our screening process. We found that CENPF expression was preferentially elevated in CRC tissues compared to adjacent normal tissues, with significantly higher levels in CRC patients with tumor recurrence. Furthermore, a multicenter cohort study demonstrated that upregulated CENPF expression was strongly associated with poorer disease-free survival in CRC. Functional experiments showed that CENPF knockdown inhibited CRC cell invasion and metastasis both in vitro and in vivo. Intriguingly, we found CENPF undergoes degradation in CRC via the ubiquitination-proteasome pathway. Mechanistically, we observed that USP4 interacted with and stabilized CENPF via deubiquitination. Furthermore, USP4-mediated CENPF upregulation was critical regulators of metastasis of CRC. Examination of clinical samples confirmed that USP4 expression positively correlates with CENPF protein expression, but not mRNA transcript levels. Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"81"},"PeriodicalIF":8.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11807140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373873","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}
Viola Melone, Domenico Palumbo, Luigi Palo, Noemi Brusco, Annamaria Salvati, Antonietta Tarallo, Giorgio Giurato, Francesca Rizzo, Giovanni Nassa, Alessandro Weisz, Roberta Tarallo
{"title":"LncRNA PVT1 links estrogen receptor alpha and the polycomb repressive complex 2 in suppression of pro-apoptotic genes in hormone-responsive breast cancer.","authors":"Viola Melone, Domenico Palumbo, Luigi Palo, Noemi Brusco, Annamaria Salvati, Antonietta Tarallo, Giorgio Giurato, Francesca Rizzo, Giovanni Nassa, Alessandro Weisz, Roberta Tarallo","doi":"10.1038/s41419-025-07423-4","DOIUrl":"10.1038/s41419-025-07423-4","url":null,"abstract":"<p><p>RNA-based therapeutics highlighted novel approaches to target either coding or noncoding molecules for multiple diseases treatment. In breast cancer (BC), a multitude of deregulated long noncoding RNAs (lncRNAs) have been identified as potential therapeutic targets also in the context of antiestrogen resistance, and the RNA binding activity of the estrogen receptor α (ERα) points additional potential candidates to interfere with estrogenic signaling. A set of lncRNAs was selected among ERα-associated RNAs in BC cell nuclei due to their roles in processes such as transcriptional regulation and epigenetic chromatin modifications. Native immunoprecipitation of nuclear ERα-interacting RNAs coupled to NGS (RIP-Seq) was performed in MCF-7 cells, leading to the identification of essential lncRNAs interacting with the receptor in multi-molecular regulatory complexes. Among these, PVT1, FGD5-AS1 and EPB41L4A-AS1 were selected for further investigation. Functional assays and transcriptome analysis following lncRNA knock-down indicated PVT1 as the master modulator of some of the most relevant BC hallmarks, such as cell proliferation, apoptosis, migration and response to hypoxia. In addition, targeted experiments identified PVT1 as a key factor in the composition of PRC2-ERα network involved in downregulation of tumor suppressor genes, including BTG2.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"80"},"PeriodicalIF":8.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11807188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373871","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}
Siddharth Sunilkumar, Sandeep M Subrahmanian, Esma I Yerlikaya, Allyson L Toro, Edward W Harhaj, Scot R Kimball, Michael D Dennis
{"title":"REDD1 expression in podocytes facilitates renal inflammation and pyroptosis in streptozotocin-induced diabetic nephropathy.","authors":"Siddharth Sunilkumar, Sandeep M Subrahmanian, Esma I Yerlikaya, Allyson L Toro, Edward W Harhaj, Scot R Kimball, Michael D Dennis","doi":"10.1038/s41419-025-07396-4","DOIUrl":"10.1038/s41419-025-07396-4","url":null,"abstract":"<p><p>Sterile inflammation resulting in an altered immune response is a key determinant of renal injury in diabetic nephropathy (DN). In this investigation, we evaluated the hypothesis that hyperglycemic conditions augment the pro-inflammatory immune response in the kidney by promoting podocyte-specific expression of the stress response protein regulated in development and DNA damage response 1 (REDD1). In support of the hypothesis, streptozotocin (STZ)-induced diabetes increased REDD1 protein abundance in the kidney concomitant with renal immune cell infiltration. In diabetic mice, administration of the SGLT2 inhibitor dapagliflozin was followed by reductions in blood glucose concentration, renal REDD1 protein abundance, and immune cell infiltration. In contrast with diabetic REDD1<sup>+/+</sup> mice, diabetic REDD1<sup>-/-</sup> mice did not exhibit albuminuria, increased pro-inflammatory factors, or renal macrophage infiltration. In cultured human podocytes, exposure to hyperglycemic conditions promoted REDD1-dependent activation of NF-κB signaling. REDD1 deletion in podocytes attenuated both the increase in chemokine expression and macrophage chemotaxis under hyperglycemic conditions. Notably, podocyte-specific REDD1 deletion prevented the pro-inflammatory immune cell infiltration in the kidneys of diabetic mice. Furthermore, exposure of podocytes to hyperglycemic conditions promoted REDD1-dependent pyroptotic cell death, evidenced by an NLRP3-mediated increase in caspase-1 activity and LDH release. REDD1 expression in podocytes was also required for an increase in pyroptosis markers in the glomeruli of diabetic mice. The data support that podocyte-specific REDD1 is necessary for chronic NF-κB activation in the context of diabetes and raises the prospect that therapies targeting podocyte-specific REDD1 may be helpful in DN.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"79"},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370545","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}
Johannes Woelk, Florian Hornsteiner, Stephanie Aschauer-Wallner, Patrizia Stoitzner, Gottfried Baier, Natascha Hermann-Kleiter
{"title":"Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6.","authors":"Johannes Woelk, Florian Hornsteiner, Stephanie Aschauer-Wallner, Patrizia Stoitzner, Gottfried Baier, Natascha Hermann-Kleiter","doi":"10.1038/s41419-025-07407-4","DOIUrl":"10.1038/s41419-025-07407-4","url":null,"abstract":"<p><p>Natural killer (NK) cell development and functionality rely on precise regulation by specific transcription factors (TFs). Our study demonstrates that the nuclear orphan receptor NR2F6 represses the expression of the activating receptor NKp46, an established key player in NK cell-mediated cytotoxicity during infection and tumor rejection. Despite normal NK cell development in the bone marrow, germline Nr2f6-deficient mice exhibit impaired terminal maturation of NK cells in the periphery. Short-term NK cell responses to lipopolysaccharide (LPS) activation, independent of NKp46, are subsequently reduced in Nr2f6-deficient mice. Conventional type 1 dendritic cells (cDC1) and macrophage populations are decreased in spleens of Nr2f6-deficient mice, subsequently, IL-15-dependent NK cell priming is limited. Administration of exogenous IL-15 in vitro and as IL-15 complex in vivo can compensate for these deficits, promoting terminal maturation of NK cells in Nr2f6-deficient mice. Subsequent transcriptome analysis reveals significant changes in gene expression profiles of NK cells from IL-15 complex treated Nr2f6-deficient mice, with notable alterations in essential NK genes such as Klrg1, Prdm1, Stat5a, Zeb2, and Prf1. Consequently, Nr2f6-deficient IL-15 complex-treated NK cells raise enhanced effector responses of IFNγ, Perforin, and Granzyme B upon ex vivo activation. Of importance, Nr2f6-deficient mice are protected against MHC-I negative B16-F10 melanoma lung metastasis formation, especially with IL-15 complex treatment, indicating the potential of NR2F6 to affect NKp46-dependent NK cell-mediated tumor surveillance. The therapeutic targeting of NR2F6 may be a promising strategy for boosting NKp46-dependent NK-cell-mediated tumor surveillance and metastasis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"77"},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370547","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}
Anya L Arthurs, Bianca Dietrich, Martin Knöfler, Caleb J Lushington, Paul Q Thomas, Fatwa Adikusuma, Jessica M Williamson, Susan Babikha, Tyla Damhuis, Tanja Jankovic-Karasoulos, Melanie D Smith, Kirsty G Pringle, Claire T Roberts
{"title":"Genetically edited human placental organoids cast new light on the role of ACE2.","authors":"Anya L Arthurs, Bianca Dietrich, Martin Knöfler, Caleb J Lushington, Paul Q Thomas, Fatwa Adikusuma, Jessica M Williamson, Susan Babikha, Tyla Damhuis, Tanja Jankovic-Karasoulos, Melanie D Smith, Kirsty G Pringle, Claire T Roberts","doi":"10.1038/s41419-025-07400-x","DOIUrl":"10.1038/s41419-025-07400-x","url":null,"abstract":"<p><p>ACE2 expression is altered in pregnancy disorders and ACE2 gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate both ACE2 knockout and ACE2 rs2074192 placental organoids, facilitating mechanistic studies into the role of ACE2 in placental development, and the effect of fetal carriage of ACE2 rs2074192 CC, CT and TT genotypes. Parameters of cell and organoid growth were measured, together with qPCR, Western Blotting, and ELISA assessments, in all groups from both organoid models. Here, we report that ACE2 knockout results in delayed placental cell growth and increased cell death. ACE2 knockout organoids had lower ACE protein expression, reduced organoid diameters and asymmetrical growth. Placental organoids with the ACE2 rs2074192 TT genotype had significantly higher expression of ACE2 mRNA and ACE2 protein with elevated ACE2:ACE expression ratio and no change in ACE protein. Despite increased expression of ACE2 protein, ACE2 enzyme activity was significantly decreased in ACE2 rs2074192 TT placental organoids. TT organoids also had reduced diameters and asymmetrical growth. Our research provides a new molecular understanding of the role of ACE2 in placental development, with potential implications for pregnancy in the carriage of the ACE2 rs2074192 gene variant.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"78"},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370540","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}
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