Neoplasia最新文献

{"title":"Prognostic role of high MTAP expression is reversed by the ERG status in prostate cancer treated by radical prostatectomy","authors":"Natalia Gorbokon ,&nbsp;Seyma Büyücek ,&nbsp;Henning Plage ,&nbsp;Neele Heckmann ,&nbsp;Ronald Simon ,&nbsp;Maximilian Lennartz ,&nbsp;Martina Kluth ,&nbsp;Katharina Teljuk ,&nbsp;Claudia Hube-Magg ,&nbsp;Sarah Minner ,&nbsp;Eike Burandt ,&nbsp;Till S. Clauditz ,&nbsp;Waldemar Wilczak ,&nbsp;Guido Sauter ,&nbsp;David Dum ,&nbsp;Andrea Hinsch ,&nbsp;Hans Heinzer ,&nbsp;Alexander Haese ,&nbsp;Thorsten Schlomm ,&nbsp;Andreas M Luebke ,&nbsp;Sarah Weinberger","doi":"10.1016/j.neo.2025.101197","DOIUrl":"10.1016/j.neo.2025.101197","url":null,"abstract":"<div><div>Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression offers a therapeutic option through synthetic lethality and confers resistance to immune checkpoint inhibitors in various cancers. To assess MTAP prevalence in prostate cancer, a tissue microarray of 17,747 samples was analyzed via immunohistochemistry. Normal prostate glands showed weak to moderate cytoplasmic MTAP staining. In 13,189 interpretable cancers, a complete loss of MTAP staining was seen in 33 (0.3 %) tumors, while MTAP staining was considered 1+ in 14.8 %, 2+ in 42.2 %, and 3+ in 42.7 % of tumors. Fluorescence in situ hybridization analysis of 9 MTAP-negative cancers confirmed homozygous MTAP deletion in all of these tumors. MTAP staining was significantly stronger in cancers harboring the <em>TMPRSS2:ERG</em> fusion than in ERG fusion negative tumors (<em>p</em> &lt; 0.0001). A comparison with clinico-pathological features revealed inverse correlations depending on the ERG fusion status: In ERG-negative cancers, high (3+) MTAP expression correlated with advanced pT stage, high Gleason grade, and early PSA recurrence (<em>p</em> &lt; 0.0001 each). Conversely, in ERG-positive tumors, MTAP expression decreased with advanced pT stage (<em>p</em> &lt; 0.0001), high classical (<em>p</em> = 0.0004) and quantitative Gleason grade (<em>p</em> = 0.0005), and low (1+) MTAP expression was significantly linked to early PSA recurrence (<em>p</em> = 0.0012). Comparison with 11 previously analyzed chromosomal deletions identified ERG-status-dependent positive or negative associations between MTAP expression and deletions of PTEN and 12p13 (<em>p</em> ≤ 0.0274), suggesting functional interactions. Taken together, the results of our study demonstrate that MTAP deficiency is exceedingly rare in prostate cancer, while high MTAP expression is a strong and independent marker for poor prognosis in ERG negative cancers.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101197"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306250","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":"SMYD2 epigenetically activates BMP4/SMAD1/5/8/ID3 axis to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma","authors":"Shanshan Wang ,&nbsp;Weicheng Wu ,&nbsp;Zhen Shi ,&nbsp;Mei Bin ,&nbsp;Fengwei Zhang ,&nbsp;Long Cai ,&nbsp;Kaiqing Lin ,&nbsp;Zhihui Li","doi":"10.1016/j.neo.2025.101203","DOIUrl":"10.1016/j.neo.2025.101203","url":null,"abstract":"<div><h3>Background</h3><div>Drug resistance prominently hampers the effects of sorafenib in hepatocellular carcinoma (HCC). Epigenetics play important roles in drug resistance. However, the contributions of SET And MYND Domain Containing 2 (SMYD2) to sorafenib resistance in HCC remain unknown. This study is aimed at elucidating the role and mechanism of SMYD2 in sorafenib resistance of HCC.</div></div><div><h3>Methods</h3><div>Using our well-established sorafenib-resistant hepatocellular carcinoma (HCC) cell lines and xenograft mouse models, we evaluated SMYD2 expression levels. To investigate the biological functions of SMYD2, we conducted a series of functional assays <em>in vitro</em> and <em>in vivo</em>. Transcriptomic profiling via RNA sequencing (RNA-seq) was performed to identify downstream targets of SMYD2. Additionally, chromatin immunoprecipitation (ChIP) assays were employed to elucidate the molecular mechanism. Correlating SMYD2 and target gene expression patterns with clinical outcomes in HCC patients was investigated.</div></div><div><h3>Results</h3><div>SMYD2 expression was significantly elevated in sorafenib-resistant HCC cells compared with parental cells. Knockdown or overexpression of SMYD2 substantially inhibited or enhanced, respectively, HCC stemness and sorafenib resistance. Mechanistically, SMYD2 promoted BMP4 expression via the maintenance of mono-methylation of histone 3 lysine 4 (H3K4me1) and di-methylation of histone 3 lysine 36 (H3K36me2) modification of its promoter. Meanwhile, knockdown or inhibition of BMP4 suppressed the stemness of sorafenib-resistant cells, inhibited the activation of SMAD1/5/8 (R-SMADs), and decreased the expression of <em>inhibitor Of DNA binding 3 (ID3)</em> gene. Moreover, BMP4 addition or ID3 reconstruction can partly reverse the effect caused by repression of SMYD2 or BMP4. HCC patients with positive co-expression of SMYD2/BMP4 or SMYD2/ID3 or SMYD2/BMP4/ID3 exhibited the worst prognosis.</div></div><div><h3>Conclusions</h3><div>Our study reveals that SMYD2 is an important epigenetic mediator that activates BMP4/R-SMADs/ID3 axis, leading to enhanced stemness and sorafenib resistance. Thus, SMYD2 might represent a potential biomarker and future epigenetic therapeutic target for sorafenib resistance of HCC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101203"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522808","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":"miRTARGET: An integrated web tool for the identification of microRNA targets with potential therapeutic or prognostic value in cancer","authors":"Matjaz Rokavec ,&nbsp;Heiko Hermeking","doi":"10.1016/j.neo.2025.101202","DOIUrl":"10.1016/j.neo.2025.101202","url":null,"abstract":"<div><div>miRTARGET (<span><span>https://www.mirtarget.com</span><svg><path></path></svg></span>) is a web tool for the identification of miRNA targets. It integrates experimental miRNA-related datasets and computational algorithms to generate prediction scores for targets of 1744 human miRNAs. The score is based on four dataset categories: mRNA profiling in cells or mice after (1) ectopic miRNA expression or (2) miRNA inactivation by knock-out or knock-down, (3) correlation analyses of mRNA and miRNA expression profiles, and (4) ten computational miRNA target prediction algorithms. Our validation analyses demonstrated a significant enrichment of published/validated miRNA targets among the predicted miRNA targets, underlining the reliability of the miRTARGET prediction score. In addition, miRTARGET integrates cancer-related datasets from primary tumors and cell lines, allowing users to filter/extract miRNA targets based on cancer cell line dependency, survival associations, and differential expression between tumor and normal tissues across 32 cancer entities. As a proof-of-concept, miRTARGET identified <em>CDC7</em> and its regulatory unit <em>DBF4</em> as the top cancer-associated predicted targets of the tumor suppressive miRNA miR-30a. Therefore, the CDC7-DBF4 complex may represent an attractive candidate therapeutic target for the treatment of cancers with miR-30a inactivation. Altogether, miRTARGET is a powerful and user-friendly web tool for exploring miRNA targets with therapeutic or prognostic potential in cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101202"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366119","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":"Biphasic behavior of T cell subsets reflects failure of early anti-myeloma response and leads to progressive T cell dysfunction","authors":"Suchita Suryakant Jadhav ,&nbsp;Vipin Sharma ,&nbsp;Aharon Lion ,&nbsp;Lasser-Katz Efrat ,&nbsp;Iftach Shaked ,&nbsp;Galia Luboshits ,&nbsp;Michael A. Firer","doi":"10.1016/j.neo.2025.101208","DOIUrl":"10.1016/j.neo.2025.101208","url":null,"abstract":"<div><h3>Introduction</h3><div>Multiple Myeloma (MM) progresses over 2-3 decades through two pre-malignant stages (MGUS and SMM), culminating in clinically active disease. Given the limitations in acquiring sequential bone marrow (BM) samples from patients over this time frame, the mechanisms that compromise immunosurveillance and promote the development of MM remain</div></div><div><h3>Methods</h3><div>Balb/c mice inoculated with MOPC315.BM myeloma cells were followed over the next 220 days. Blood and bone marrow samples were collected on days 80, 150, and 220 post cell inoculation. Blood samples were used to monitor levels of paraprotein and whole blood cell counts. BM aspirates were used for deep immune profiling by flow cytometry and for T cell function assays.</div></div><div><h3>Results</h3><div>Blood analyses validated that the model reflects serological features of human MM. Analysis of BM samples revealed a biphasic behavior of T regulatory cells, Th17 cells, CD8+ cytotoxic T cells and NK cells, as well as skewing of CD4+ and CD8+ T memory cell subset distributionss, suggesting failure of an early anti-myeloma response, which is replaced by progressive immunosuppression, and dysfunction and exhaustion of CD8+ T cell tumor cytotoxicity.</div></div><div><h3>Conclusion</h3><div>Our new model is a flexible tool to investigate the early cellular interactions that initiate immunosuppression and MM disease progression. The model can also be used to test the efficacy of new therapeutic strategies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101208"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597484","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":"The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression","authors":"Kirsten Brooksbank ,&nbsp;Charlotte Smith ,&nbsp;Eleni Maniati ,&nbsp;Amy Gibson ,&nbsp;Wai Yiu Tse ,&nbsp;Amy Kate Hall ,&nbsp;Jun Wang ,&nbsp;Tyson V Sharp ,&nbsp;Sarah A Martin","doi":"10.1016/j.neo.2025.101207","DOIUrl":"10.1016/j.neo.2025.101207","url":null,"abstract":"<div><div>Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ∼50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the different MMR genes. Here, we show that increased PD-L1 expression is observed upon loss of the MMR genes MLH1, MSH2 and PMS2. However, this is not true upon loss of MSH6, and we show that this is due to a novel role for MSH6 as a direct regulator of PD-L1 transcription, dependent on recruitment by the histone trimethyltransferase SETD2. Next-generation sequencing of MLH1 and MSH6 knockout (KO) cells revealed that MSH6 KO cells have significantly lower microsatellite instability in comparison to MLH1 KO cells, despite MSH6 KO cells having a higher mutational burden. These findings emphasise the need for gene-specific stratification in the MMRd cohort.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101207"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597485","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":"ACSL4 knockdown inhibits colorectal cancer progression through stimulating anti-tumor immunity","authors":"Yiming Liu ,&nbsp;Xingyu Jiang ,&nbsp;Dongquan Jing ,&nbsp;Yanting Lin ,&nbsp;Rui Gao ,&nbsp;Qixiang Zhao ,&nbsp;Huijuan Da ,&nbsp;Yiming Ren ,&nbsp;Qiuhua Cao ,&nbsp;Ning Liu ,&nbsp;Xiaoyun Han ,&nbsp;Juan Du ,&nbsp;Xinghua Gao","doi":"10.1016/j.neo.2025.101194","DOIUrl":"10.1016/j.neo.2025.101194","url":null,"abstract":"<div><div>Background: Long-chain acyl-CoA synthetase 4 (ACSL4), a crucial modulator of ferroptosis, is associated with tumor progression, though its impact on <strong>colorectal cancer (</strong>CRC) immune dynamics is not fully understood.</div><div>Methods: ACSL4 expression was analyzed in CRC tissues and correlated with patient prognosis. Effects of ACSL4 were evaluated in CRC cells in vitro and in subcutaneous and orthotopic CRC models. Flow cytometry and immunofluorescence were used to evaluate immune cell infiltration. RNA sequencing and RT-PCR were employed to identify ACSL4-regulated signaling pathways. The effect of ACSL4 silencing on PD-L1 blockade efficacy was also examined.</div><div>Results: ACSL4 levels were markedly increased in CRC and linked to unfavorable patient outcomes. While <em>ACSL4</em> knockdown had no direct effect on CRC cell proliferation, it significantly suppressed tumor growth in immunocompetent mice. ACSL4 depletion enhanced CD3⁺ and CD8⁺ T cell infiltration and upregulated chemokines (CXCL10, CXCL11) and antigen presentation genes (H2k1, TAP1, TAPBP). Transcriptomic analysis highlighted activation of the RIG-I-MAVS-driven type I interferon pathway. Co-culture assays demonstrated that <em>ACSL4</em> knockdown promoted CD8⁺ T cell activation, and ACSL4-deficient tumors exhibited enhanced responsiveness to PD-L1 blockade.</div><div>Conclusions: ACSL4 suppresses anti-tumor immunity in CRC by modulating the RIG-I-MAVS-IFN pathway, highlighting ACSL4 as a promising target for CRC immunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101194"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253315","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":"Rezatapopt: A promising small-molecule “refolder” specific for TP53Y220C mutant tumors","authors":"Kostas A. Papavassiliou ,&nbsp;Alice G. Vassiliou ,&nbsp;Athanasios G. Papavassiliou","doi":"10.1016/j.neo.2025.101201","DOIUrl":"10.1016/j.neo.2025.101201","url":null,"abstract":"<div><div>Inactivation of p53 due to mutation is observed in approximately half of all human cancer cases, therefore, restoration of the tumor suppressor function of oncogenic p53 mutants represents an attractive and rational therapeutic approach. Currently, multiple mutant p53 reactivators have been developed, but only a handful have entered clinical trials [<span><span>1</span></span>]. PC14586 (rezatapopt) is an orally available small-molecule reactivator of the Y220C-mutant p53 protein that showed preliminary efficacy and a favorable safety profile in a phase I clinical trial [<span><span>2</span></span>] and is now undergoing evaluation in a phase II clinical trial in patients with advanced solid tumors harboring the <em>TP53</em>^Y220C mutation (NCT04585750). Although rezatapopt and other p53 mutant reactivators are under clinical assessment, there are still many knowledge gaps that need to be filled to unleash their full therapeutic potential.</div><div>The preclinical data presented in a recently published research article by Puzio-Kuter et al. achieve to enhance our understanding of the mechanisms and effects of p53-Y220C reactivator compounds and underscore the potential of targeting p53 mutants in cancer therapy [<span><span>3</span></span>]. Through this spotlight article, we aim to summarize the findings and emphasize the clinical implications of the study by Puzio-Kutler et al.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101201"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321683","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":"Tumor neoantigens as key drivers of significant anti - tumor immunity in triple - negative breast cancer mouse models","authors":"Yujeong Her ,&nbsp;Jeong Yeon Kim ,&nbsp;Hocheol Shin ,&nbsp;Kwangmin Yu ,&nbsp;Kyu-Jin Lee ,&nbsp;Yi Rang Na ,&nbsp;Sangyong Jon ,&nbsp;Jung Kyoon Choi ,&nbsp;Hyeong-Gon Moon","doi":"10.1016/j.neo.2025.101205","DOIUrl":"10.1016/j.neo.2025.101205","url":null,"abstract":"<div><div>Recent studies have highlighted the therapeutic potential of targeting tumor neoantigens in solid tumors; however, its efficacy in breast cancer remains unclear. Here, we evaluate the impact of tumor neoantigen-targeted strategies in a syngeneic mouse mammary carcinoma model. Mice previously exposed to 4T1 tumor cells (PETCs) or treated with tumor cell-derived lysates (TdLs) exhibited robust antitumor immunity, leading to reduced tumor growth and metastasis through tumor immune microenvironment remodeling. TdL administration in mice harboring orthotopic tumors significantly enhanced the efficacy of immune checkpoint blockade, suggesting its potential as an immunotherapeutic adjuvant. To further optimize neoantigen-based approaches, we developed a lipid nanoparticle (LNP)-based delivery system for neoantigen peptides, which effectively suppressed tumor progression and metastasis in vivo. Mechanistically, this strategy promoted antigen-specific T cell activation and reshaped the tumor immune landscape, enhancing immune-mediated tumor rejection. These findings underscore the therapeutic promise of personalized tumor neoantigen-targeted immunotherapy in breast cancer and support its further evaluation in clinical settings.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101205"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572429","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":"DHX34 deficiency triggers tumor-intrinsic immunity via a dsRNA-mediated type I interferon pathway activation in HCC","authors":"Chunli Zhang ,&nbsp;Limin Huang ,&nbsp;Zeyu Li ,&nbsp;Qian Wang ,&nbsp;Nanbin Liu ,&nbsp;Chongyu Zhang ,&nbsp;Xi Liu ,&nbsp;Chen Zhang ,&nbsp;Gaixia He ,&nbsp;Jin Sun ,&nbsp;Zongfang Li ,&nbsp;Hongwei Tian","doi":"10.1016/j.neo.2025.101198","DOIUrl":"10.1016/j.neo.2025.101198","url":null,"abstract":"<div><div>Tumors often evade immune surveillance by crippling their immunogenicity in the microenvironment. DHX34, an RNA helicase involved in nonsense-mediated mRNA decay pathway, is critical for aberrant RNA degradation. However, the effect of DHX34 in regulating the immunogenicity in hepatocellular carcinoma (HCC) is still unclear. Here, a surprising function of DHX34 in inhibited HCC immunogenicity is identified. DHX34-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, DHX34 depletion triggered dsRNA accumulation which may activate cytosolic RNA-sensing pathway effectors such as <em>MAVS, p-IKK, p-IRF3</em>, and the subsequent type-I interferon response, evoking tumor-intrinsic immunity and leading to CD8 T activation. Collectively, DHX34 is implicated as a regulator that orchestrates a barrier in HCC by suppressing dsRNA-driven innate immune activation. Targeting DHX34 may enhance tumor immunogenicity and synergize with immunotherapies, offering a novel therapeutic strategy for HCC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101198"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518129","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":"SKI regulates rRNA transcription and pericentromeric heterochromatin to ensure centromere integrity and genome stability","authors":"Víctor Pola-Véliz ,&nbsp;David Carrero ,&nbsp;Eduardo A. Sagredo ,&nbsp;Víctor Inostroza ,&nbsp;Claudio Cappelli ,&nbsp;Solange Rivas ,&nbsp;Mirit Bitrán ,&nbsp;Evelyn Zambrano ,&nbsp;Evelin Gonzalez ,&nbsp;Fernanda Morales ,&nbsp;Marcia Manterola ,&nbsp;Martín Montecino ,&nbsp;Ricardo Armisén ,&nbsp;Katherine Marcelain","doi":"10.1016/j.neo.2025.101204","DOIUrl":"10.1016/j.neo.2025.101204","url":null,"abstract":"<div><div>Accurate chromosome segregation and ribosomal gene expression silencing are essential for maintaining genome integrity, and disruptions in these processes are key for oncogenesis and cancer progression. Here, we demonstrate a novel role for the transcriptional co-repressor SKI in regulating rDNA and pericentromeric heterochromatin (PCH) silencing in human cells. We found that SKI localizes to the rDNA promoter on acrocentric chromosomes and is crucial for maintaining H3K9 trimethylation (H3K9me3) and repressing 45S rRNA gene expression. SKI is also associated with BSR and HSATII satellites within PCH, where is necessary for H3K9 methylation and recruitment of SUV39H1 and HP1α, key players for heterochromatin silencing and centromere function. Consequently, SKI deficiency disrupted centromere integrity and resulted in aberrant chromosome segregation, micronuclei formation, and chromosome instability. The identification of SKI as a key participant in the epigenetic-mediated silencing of pericentromeric and ribosomal DNA provides a fundamental insight, paving the way for new research into the intricate relationship between transcriptional regulation and genome instability during cancer progression, and opening novel opportunities for therapeutic intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101204"},"PeriodicalIF":4.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523008","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}