IUBMB Life最新文献

{"title":"Purification and validation of asparaginyl-tRNA synthetase heterodimer with indistinguishable subunits","authors":"Ingrid Vallee,&nbsp;Ryan Shapiro,&nbsp;Xiang-Lei Yang","doi":"10.1002/iub.70000","DOIUrl":"https://doi.org/10.1002/iub.70000","url":null,"abstract":"<p>Oligomerization can influence the stability and activity of a protein. The majority of enzymes, including aminoacyl-tRNA synthetases, become catalytically active upon forming homodimers. Residues located at the dimerization interface are highly conserved and mutations arising within can cause severe disease phenotypes. Beyond homozygous mutations, other disease-causing mutations, such as compound heterozygous and mono-allelic mutations, can lead to the formation of heterodimers between two distinct subunits. Purifying a recombinant heterodimer is required for its thorough characterization in vitro, yet there is a lack of established biochemical methods for the preparation. Here we describe a heterodimer purification and validation method with the example of a disease-causing mono-allelic, nonsense mutation R534* in cytoplasmic asparaginyl-tRNA synthetase (NARS1 or AsnRS). Our method involves co-expression of two separately tagged constructs to allow for purification of the wild-type and the R534* mutant heterodimers. While the two subunits can hardly be distinguished by size, their separate detection is achieved by western blotting against the tags. Quantification analysis confirmed that the subunits within the heterodimer are present in nearly equal proportions. This simple protocol can be adapted to study other size-indistinguishable heterodimers.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced HER2 status detection in breast and gastric cancers using surrogate DNA methylation markers","authors":"Yajie Hu,&nbsp;Siyu Liu,&nbsp;Chunhui Cui,&nbsp;Xin Liu,&nbsp;Hui Li,&nbsp;Hong Liu,&nbsp;Shiyao Lu,&nbsp;Zhipeng Lu,&nbsp;Zhiwei Chen,&nbsp;Da Pang,&nbsp;Jian-Bing Fan,&nbsp;Dongmei Lin,&nbsp;Xianyu Zhang,&nbsp;Yu Sun","doi":"10.1002/iub.70004","DOIUrl":"https://doi.org/10.1002/iub.70004","url":null,"abstract":"<p>There is a limited understanding of specific DNA methylation patterns associated with HER2 overexpression in breast and gastric cancers. Here we aim to solve the problem using inferred DNA methylation markers. DNA methylation data from The Cancer Genome Atlas (TCGA) were analyzed for breast and gastric cancers regarding HER2 status. We further applied a targeted bisulfite sequencing approach to elaborate the DNA methylation profile of the <i>HER2</i> region, covering 7635 CpG sites. Based on these two sets of data, we selected specific DNA methylation markers inferring HER2 status for both breast and gastric cancers and validated their performance in assisting HER2-status determination on a retrospective cohort with 496 breast cancer and 372 gastric cancer. HER2-Meth could well distinguish HER2 IHC0/1+ from HER2 IHC3+ cases in both breast cancer (AUC = 0.983, <i>n</i> = 130) and gastric cancer (AUC = 0.974, <i>n</i> = 63), also could effectively discriminate HER2 IHC2+/FISH+ from HER2 IHC2+/FISH- cases in equivocal situations for both breast cancer (test set AUC = 0.879, <i>n</i> = 74; validation set AUC = 0.875, n = 75) and gastric cancer (test set AUC = 0.910, <i>n</i> = 70; validation set AUC = 0.941, n = 71), outperforming regular <i>HER2</i> copy number test (An AUC of 0.793 for breast cancer and an AUC of 0.759 for gastric cancer) on HER2 IHC2+ cases. Furthermore, HER2-Meth demonstrated its potential for stratifying HER2-positive patients, enabling predictions regarding overall survivals, and the potential benefits of HER2-targeted therapies in breast cancer. The strong agreement observed between the methylation qPCR test and the results of IHC and FISH indicates significant potential for this approach as a complementary tool in guiding HER2-targeted therapies for patients with breast and gastric cancers.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia inducible factor 3-alpha promotes a malignant phenotype in colorectal cancer cells","authors":"Alejandro Lopez-Mejia,&nbsp;Angela Patricia Moreno-Londoño,&nbsp;Gabriela Fonseca Camarillo,&nbsp;Jesús Kazuo Yamamoto-Furusho,&nbsp;Juan Antonio Villanueva-Herrero,&nbsp;Jorge Luis de Leon-Rendón,&nbsp;Maria Cristina Castañeda Patlán,&nbsp;Martha Robles-Flores","doi":"10.1002/iub.70007","DOIUrl":"https://doi.org/10.1002/iub.70007","url":null,"abstract":"<p>Colorectal cancer (CRC) is the third most common cancer worldwide. Hypoxia is a hallmark of the tumor microenvironment, and cellular adaptation to it is primarily mediated by the family of Hypoxia-inducible factors (HIFs) HIF-1α, HIF-2α, and HIF-3α. However, in contrast to HIF-1α and HIF-2α, a specific role for HIF-3α in cancer biology has not yet been clearly established. This research was aimed to elucidate the role of HIF-3α in colon cancer. As reported previously for HIF-1α and HIF-2α, we found that HIF-3α is also overexpressed under normoxic conditions in all cancer cell lines examined and in patient-derived tumor tissue samples compared with non-malignant cells and normal tissue, but remarkably, pulse-chase experiments demonstrated that HIF-3α displays high stability in cells compared with HIF-1α and HIF-2α. <i>Progno Scan</i> data analysis showed that overexpression of HIF-3α correlated with a patient's lower survival rate and a poor prognosis in colon adenocarcinoma patients. Knockdown of HIF-3α expression was carried out to investigate the effects derived from its silencing on malignant phenotype. We found a significative decrease in the Hypoxia Response Element (HRE) reporter transcriptional activity mediated by HIF-3α and a reduction in cell viability under oxidative stress in colon cancer cells with HIF-3α knockdown compared with control HIF-3α expressing cells. In addition, HIF-3α silencing also produced an increase in apoptotic rate, decreased clonogenic capacity, altered autophagy flux, and modulated the canonical Wnt/β pathway in an isoform-dependent and cell context-dependent manner in colon cancer cells. Overall, these data show that transcriptional activity mediated by HI3-3α plays an essential role in promoting the malignant phenotype, cell survival, and resistance to cell death in CRC cells.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adverse fetal and neonatal impact of war conflicts during pregnancy: A systematic review","authors":"Blanca Riquelme-Gallego,&nbsp;Lucía Ramos-Soberbio,&nbsp;Ester Leno-Duran,&nbsp;Sergio Martínez-Vázquez,&nbsp;Rafael A. Caparros-Gonzalez","doi":"10.1002/iub.70006","DOIUrl":"https://doi.org/10.1002/iub.70006","url":null,"abstract":"<p>The aim of the present study was to establish the fetal and neonatal impact of war conflicts during pregnancy. A systematic review was conducted according to The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and relevant publications available in the PubMed, Scopus and Web of Science, and PsycINFO databases. Primary and quantitative studies were eligible for inclusion. To be included, studies had to be redacted in Spanish or English and evaluate maternal exposure to a war or terrorist attack during pregnancy, with consideration being given of the consequences of this for fetal and/or neonatal development. Systematic, narrative and exploratory literature reviews were excluded, as were meta-analyses and studies in which the sample differed from the sample of interest, the focus was on other stressful factors that differed from a war conflict and the consequences examined did not comprise the impact of a war during pregnancy on the fetus or neonate. The methodological quality of included articles was assessed using the CASP (Critical Appraisal Skills Programme) tool. A total of 28 articles were included, with an included sample of <i>n</i> = 664,980 mother-infant dyads, exposed to war conflicts. The adverse impact of prenatal stress suffered by mothers during periods of war revealed that, (1) in the short-term, babies were at greater risk of having a low birth weight and impinged length and being born prematurely, whilst mothers were more likely to suffer a miscarriage. (2) In the long-term, babies exposed to war during the prenatal period had a higher risk of experiencing alterations to their neurodevelopment, mental disorders and pathophysiological diseases. The stress suffered by mothers during the prenatal period can bring about a number of negative consequences over both the short- and long-term in babies, especially, in terms of their physical and neurological development. It is important to conduct further research on the topic with the aim of detecting and treating the early stages of maternal psychological illnesses experienced during pregnancy due to war conflict and, in this way, achieve benefits for pregnant women and future generations.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure–function relationships between the human bitter taste receptor TAS2R38 and propylthiouracil: An in-silico investigation","authors":"Gowtham Subramanian,&nbsp;Vinithra Ponnusamy,&nbsp;Janaranjani Murugesan,&nbsp;Hemamalini Vedagiri,&nbsp;Prabha Panneerselvan,&nbsp;Keerthana Vasanthakumar,&nbsp;Vasanth Krishnan,&nbsp;Selvakumar Subramaniam","doi":"10.1002/iub.70008","DOIUrl":"https://doi.org/10.1002/iub.70008","url":null,"abstract":"<p>Taster categorisation uses bitter thiourea compounds like propylthiouracil (PROP) and phenylthiocarbamide (PTC), which are frequently associated with amino acid alterations at positions 49, 262 and 296 in human taste 2 receptor member 38 (hTAS2R38). Since the hTAS2R38 protein lacked a crystallographic structure, it was modelled using contact-guided iterative threading assembly refinement, its residues were mutated and refined, and the binding pocket area and volume were assessed using CASTp. Bitter thiourea molecules were docked using the ligand extra precision module and the receptor–ligand complex was manually positioned in a fully hydrated, equilibrated 1-palmitoyl-2-oleoylphosphatidylcholine bilayer using the CHARMM GUI membrane constructor, a 100 ns simulation was carried out using the Desmond program. Analysis revealed that the PROP binds to the allosteric hydrophobic pocket of hTAS2R38 and forms a hydrogen bond with ASN190. The native structure (hTAS2R38_PAV) has a higher glide energy (−24.164 kcal/mol) and docking score (−7.212 kcal/mol) than mutants, corroborating our taste preference study. In contrast, PTC lacks hydrogen bonds in the binding pocket but exhibits pi–pi stacking interactions with the native structure. Structures with mutations at the 49th or 296th position showed the largest root mean square deviations and fluctuations. A triple mutation increases surface area and volume, making the 262nd position critical to the binding pocket. These results highlight the functional roles of these three residues in hTAS2R38.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells”","authors":"","doi":"10.1002/iub.70005","DOIUrl":"https://doi.org/10.1002/iub.70005","url":null,"abstract":"<p>\u0000 <span>M. F. Tolba</span>, <span>A. Esmat</span>, <span>A. M. Al-Abd</span>, <span>S. S. Azab</span>, <span>A. E. Khalifa</span>, <span>H. A. Mosli</span>, <span>S. Z. Abdel-Rahman</span>, and <span>A. B. Abdel-Naim</span>, “ <span>Caffeic acid phenethyl Ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells</span>,” <i>IUBMB Life</i> <span>65</span>, no. <span>8</span> (<span>2013</span>): <span>716</span>–<span>729</span>, https://doi.org/10.1002/iub.1188.</p><p>Concerns were raised by a third party regarding duplication of image panels within the article (Figures 3 and 8). An investigation by the journal team confirmed these issues and discovered another instance of duplication between Figure 4A and B GAPDH panels.</p><p>The authors admitted to the image compilation errors in Figures 3 and 8. Regarding Figure 4, they stated that the samples and their controls were obtained from the same PCR/gel electrophoresis run. The authors cooperated with the investigation, however, the partial raw data provided were not sufficient to fully address the concerns; therefore, they repeated the experiments in question to provide further clarification.</p><p>The new data confirmed the same trends as observed before, therefore, the experimental results and the corresponding conclusions of the paper remain unaffected.</p><p>The corrected Figures 3, 4, and 8 and their corrected captions are as follows:</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic landscaping of receptor tyrosine kinase ALK with highly frequent rearrangements in cancers","authors":"Wei Ye,&nbsp;Wen-Bin Ou","doi":"10.1002/iub.70003","DOIUrl":"https://doi.org/10.1002/iub.70003","url":null,"abstract":"<p>Anaplastic lymphoma kinase (ALK) fusion tyrosine kinases (TKs) are commonly found in various cancers and are considered as promising targets for therapy due to their intricate biological processes. However, the reasons for the higher frequency of ALKs fusion compared to other TKs are not well elucidated. Physicochemical properties, secondary and tertiary structures, and phylogenetic trees, along with protein sequence alignments of receptor tyrosine kinases (RTKs) and ALK fused partner genes, were examined using the resources provided by the National Center for Biotechnology Information (NCBI) and the Catalogue of Somatic Mutations in Cancer (COSMIC). Sequence alignments were performed to identify common sequences between partner genes and search for common breakpoints within the COSMIC database. ALK is a large, unstable, acidic protein with similarly conservation among RTKs. ALK fusion partners are mostly acidic, unstable proteins, mostly consisting of α-helices and random coil. However, <i>EML4</i> and <i>NPM1</i> are the most frequently occurring partner genes and have their own unique structural characteristics. By functional domain analysis, we found that the functions of the first half of the <i>ALK</i> partner gene (the part fused to ALK) are mostly focused on signaling. ALK is identified as a large hydrophilic protein，exhibits a higher proportion of random coils. Compared to other RTKs, ALK has fewer structural domains (PTKC_ALK_LTK domain). Pairwise comparison with fusion partner genes revealed a conserved sequence predicted to have structural stability and act as a common binding site for nucleases. Exon 20 of <i>ALK</i> is a fusion frequent site according to COSMIC database analysis. The structural instability of ALK and partner genes, coupled with the inherent variability of breakpoint sequences, leads to the formation of potent kinase-activated oncogenes, which play a critical role in tumorigenesis. While the occurrence of <i>ALK</i> fusions with partner genes is random, specific combinations lead to the generation of oncogenes.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Possible new mechanisms of primary drug resistance in NSCLC with EGFR mutation treated with Osimertinib","authors":"Lujing Shao,&nbsp;Tong Li,&nbsp;Xinyan Jia,&nbsp;Xinyu Zhang,&nbsp;Qi Li,&nbsp;Chunyan Dong","doi":"10.1002/iub.70002","DOIUrl":"10.1002/iub.70002","url":null,"abstract":"<p>In this study, a patient with lung adenocarcinoma harboring an EGFR mutation exhibited primary resistance to the targeted EGFR inhibitor Osimertinib after 2 months of treatment. As the disease advanced, further genetic analysis revealed the emergence of additional mutations in ARID1A, NTRK1, and ZRSR2, alongside the existing EGFR mutation. Subsequent treatment with Pemetrexed resulted in a significant reduction in liver metastases. Protein mass spectrometry sequencing and immunohistochemical analysis collectively indicated that the PI3K/mTOR pathway mediates the mechanism through which these gene mutations confer primary drug resistance. Evidence demonstrates that the co-occurrence of EGFR and ARID1A mutations diminishes the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Consequently, it is hypothesized that mutations in NTRK1 and ZRSR2, which are implicated in the PI3K/mTOR pathway, contribute to the primary resistance observed with Osimertinib treatment. In this case, the illness was effectively managed through prompt adjustments to the treatment regimen and the rapid administration of chemotherapy drugs. This finding also constitutes the first evidence that mutations in NTRK1 and ZRSR2 are pivotal in the development of primary resistance to Osimertinib. Consequently, it is imperative to conduct genetic testing at the earliest opportunity and modify the treatment plan accordingly.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc finger protein 169 promotes tumor progress of hepatocellular cancer via up-regulating cyclin-dependent kinase 19","authors":"Chaoquan Hu,&nbsp;Aizier Ainiwaer,&nbsp;Ying Lu,&nbsp;Jiaxing Li,&nbsp;Yongmei Fu,&nbsp;Jun Luo,&nbsp;Baijun Wu,&nbsp;Peng Yin,&nbsp;Xiao Hu,&nbsp;Yao Sun,&nbsp;Hong Li,&nbsp;He Lu,&nbsp;Zheng Dong","doi":"10.1002/iub.2943","DOIUrl":"10.1002/iub.2943","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer globally. Zinc finger protein 169 (ZNF169) holds significant importance as a transcription factor, yet its precise function in HCC remains to be elucidated. This study aims to examine the clinical importance, biological functions, and molecular pathways associated with ZNF169 in the development of HCC. The study employed lentiviral transduction for ZNF169 overexpression and the use of small interfering RNAs (siRNAs) to suppress its expression. ZNF169 was upregulated in HCC tissues and cell lines. Additionally, HCC patients exhibiting elevated ZNF169 levels experienced reduced overall survival, shorter disease-free survival, and diminished progression-free survival. Silencing of ZNF169 inhibited cell proliferation, migration, and cell cycle progression. Whereas ectopic expression of ZNF169 promoted HCC progression in vivo and ex vivo. Subsequently, Pearson analysis results showed that cyclin-dependent kinase 19 (CDK19) was positively correlated with ZNF169 levels in HCC using TCGA dataset. Luciferase assay findings indicated a potential interaction between ZNF169 and CDK19 promoter. Additionally, our data showed that CDK19 expression levels were elevated in HCC tissues, and patients with higher CDK19 expression faced a poorer prognosis. Furthermore, recovery experiments demonstrated that CDK19 could reverse the impact of ZNF169 on HCC cell amplification. Our findings indicate that ZNF169 promotes HCC progression by upregulating CDK19, highlighting its role as a therapeutic target or prognostic biomarker for HCC.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDKN3 as a key regulator of G2M phase in triple-negative breast cancer: Insights from multi-transcriptomic analysis","authors":"Haodi Ma,&nbsp;Yirui Dong,&nbsp;Jiayu Zheng,&nbsp;Shunshun Zhang,&nbsp;Siya Tang,&nbsp;Junxiang Wang,&nbsp;Zhifeng Qu,&nbsp;Xiucheng Li,&nbsp;Li Zeng,&nbsp;Kena Song,&nbsp;Chunyan Liu,&nbsp;Linlin Shi,&nbsp;Qinan Yin,&nbsp;Xuewei Zheng","doi":"10.1002/iub.2922","DOIUrl":"10.1002/iub.2922","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) remains a significant global health challenge, emphasizing the need for precise identification of patients with specific therapeutic targets and those at high risk of metastasis. This study aimed to identify novel therapeutic targets for personalized treatment of TNBC patients by elucidating their roles in cell cycle regulation. Using weighted gene co-expression network analysis (WGCNA), we identified 83 hub genes by integrating gene expression profiles with clinical pathological grades. A machine learning-based integrative approach further pinpointed 12 prognostic genes, among which CDKN3 exhibited the highest hazard ratio and the most adverse impact on overall survival (OS) in BC patients. Additionally, CDKN3 was identified as an independent prognostic factor for OS prediction. CDKN3 overexpression was confirmed in BC patients and validated at both mRNA and protein levels in BC cells. Knockdown of CDKN3 significantly inhibited the migration and proliferation of BC cells. Cell cycle pathway analysis revealed significant enrichment in G2M-associated pathways in BC patients, with multi-transcriptomic data indicating a close association between enhanced G2M cell cycle activity and CDKN3 upregulation in basal cancer subtypes. Pseudotime analysis further suggested CDKN3 upregulation during the G2M phase at the terminal trajectory of basal cancer subtypes, implying that CDKN3 may drive BC cell progression by promoting G2M cell cycle activity. Mechanistically, CDKN3 knockdown induced G2M cell cycle arrest in TNBC cells by downregulating CCNB2. In conclusion, CDKN3 knockdown effectively inhibits TNBC by arresting the G2M cell cycle, underscoring CDKN3 as a promising therapeutic target in TNBC treatment.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}