NAR cancer最新文献

{"title":"GSK-3484862, a DNMT1 degrader, promotes <i>DNMT3B</i> expression in lung cancer cells.","authors":"Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng","doi":"10.1093/narcan/zcaf018","DOIUrl":"10.1093/narcan/zcaf018","url":null,"abstract":"<p><p>DNA methylation alterations, including hypermethylation and silencing of tumor suppressor genes, contribute to cancer formation and progression. The FDA-approved nucleoside analogs azacytidine and decitabine are effective demethylating agents for hematologic malignancies but their general use has been limited by their toxicity and ineffectiveness against solid tumors. GSK-3484862, a dicyanopyridine-containing, DNMT1-selective inhibitor and degrader, offers a promising lead for developing novel demethylating therapeutics. Here, we demonstrate that GSK-3484862 treatment upregulates <i>DNMT3B</i> expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting <i>DNMT3B</i> in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces demethylation at <i>DNMT3B</i> regulatory elements including a candidate enhancer located ∼10 kb upstream of the <i>DNMT3B</i> transcription start site, as well as at the promoter of <i>TERT</i> (telomerase reverse transcriptase), a potential activator of <i>DNMT3B</i> expression. These demethylation events correlate with upregulation of <i>DNMT3B</i> expression. These findings suggest that combining inhibitors targeting DNMT1, the maintenance methyltransferase, with those targeting DNMT3A/3B, the <i>de novo</i> methyltransferases, or using pan-DNMT inhibitors, could enhance anticancer efficacy and reduce resistance.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf018"},"PeriodicalIF":3.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix stiffness modulates androgen response genes and chromatin state in prostate cancer.","authors":"Roosa Kaarijärvi, Heidi Kaljunen, Onni Niemi, Merja Räsänen, Ville Paakinaho, Kirsi Ketola","doi":"10.1093/narcan/zcaf010","DOIUrl":"10.1093/narcan/zcaf010","url":null,"abstract":"<p><p>The interplay between the extracellular matrix (ECM) and prostate cancer has been shown to increase ECM stiffness, correlating with more aggressive disease forms. However, the impact of ECM stiffness on the androgen receptor (AR), a key target in prostate cancer treatment, remains elusive. Here, we investigated whether matrix stiffness influences prostate cancer progression, transcriptional regulation, chromatin state, and AR function in AR-positive prostate cancer cells under varying ECM stiffness conditions. We utilized ATAC-seq (assay for transposase-accessible chromatin with sequencing) and RNA sequencing under different ECM conditions, along with the SUC2 metastatic prostate adenocarcinoma patient dataset, to investigate the role of ECM stiffness in chromatin state and androgen response genes, as well as its impact on prostate cancer progression. Results demonstrated that increased ECM stiffness elevated the expression of genes related to proliferation and differentiation. In contrast, androgen response genes were most highly induced in soft ECM conditions. Integrating chromatin accessibility with transcriptomic data revealed that androgen response genes were more transcriptionally available in soft ECM conditions. Additionally, increased ECM stiffness upregulated genes associated with low overall survival in the SUC2 dataset. Taken together, our results indicate that high expression of hard matrix stiffness genes may promote prostate cancer progression, leading to more aggressive disease forms associated with poor survival.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf010"},"PeriodicalIF":3.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIP13 protects pancreatic cancer cells against intrinsic and therapy-induced DNA replication stress.","authors":"Jay R Anand, Gaith N Droby, Sayali Joseph, Urvi Patel, Xingyuan Zhang, Jeffrey A Klomp, Channing J Der, Jeremy E Purvis, Samuel C Wolff, Jessica L Bowser, Cyrus Vaziri","doi":"10.1093/narcan/zcaf009","DOIUrl":"10.1093/narcan/zcaf009","url":null,"abstract":"<p><p>Oncogene activation in normal untransformed cells induces DNA replication stress and creates a dependency on DNA damage response (DDR) mechanisms for cell survival. Different oncogenic stimuli signal via distinct mechanisms in every cancer setting. The DDR is also pathologically reprogrammed and deployed in diverse ways in different cancers. Because mutant KRAS is the driver oncogene in 90% of pancreatic ductal adenocarcinomas (PDACs), here we have investigated DDR mechanisms by which KRAS-induced DNA replication stress is tolerated in normal human pancreatic epithelial cells [human pancreatic nestin-expressing (HPNE) cells]. Using a candidate screening approach, we identify TRIP13 as a KRAS^G12V-induced messenger RNA that is also expressed at high levels in PDAC relative to normal tissues. Using genetic and pharmacological tools, we show that TRIP13 is necessary to sustain ongoing DNA synthesis and viability specifically in KRAS^G12V-expressing cells. TRIP13 promotes survival of KRAS^G12V-expressing HPNE cells in a homologous recombination (HR)-dependent manner. KRAS^G12V-expressing HPNE cells lacking TRIP13 acquire hallmark HR deficiency phenotypes, including sensitivity to inhibitors of translesion synthesis and poly-ADP ribose polymerase. Established PDAC cell lines are also sensitized to intrinsic DNA damage and therapy-induced genotoxicity following TRIP13 depletion. Taken together, our results expose TRIP13 as an attractive new and therapeutically tractable vulnerability of KRAS-mutant PDAC.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf009"},"PeriodicalIF":3.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optical genome and epigenome mapping of clear cell renal cell carcinoma.","authors":"Sapir Margalit, Zuzana Tulpová, Yael Michaeli, Tahir Detinis Zur, Jasline Deek, Sivan Louzoun-Zada, Gil Nifker, Assaf Grunwald, Yuval Scher, Leonie Schütz, Elmar Weinhold, Yehudit Gnatek, Dorit Omer, Benjamin Dekel, Eitan Friedman, Yuval Ebenstein","doi":"10.1093/narcan/zcaf008","DOIUrl":"10.1093/narcan/zcaf008","url":null,"abstract":"<p><p>Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel-Lindau (<i>VHL</i>) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes <i>VHL</i>, <i>PRCC</i>, and <i>PBRM1</i>. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf008"},"PeriodicalIF":3.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11886815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment.","authors":"Roderic Espín, Ferran Medina-Jover, Javier Sigüenza-Andrade, Sònia Farran-Matas, Francesca Mateo, Agnes Figueras, Rosario T Sanz, Guillermo Pablo Vicent, Arzoo Shabbir, Lara Ruiz-Auladell, Emilio Racionero-Andrés, Irene García, Alexandra Baiges, Lídia Franco-Luzón, Adrián Martínez-Tebar, Miguel Angel Pardo-Cea, María Martínez-Iniesta, Xieng Chen Wang, Elisabet Cuyàs, Javier A Menendez, Marta Lopez-Cerda, Purificacion Muñoz, Ivonne Richaud, Angel Raya, Isabel Fabregat, Alberto Villanueva, Xènia Serrat, Julián Cerón, Montserrat Alemany, Inés Guix, Andrea Herencia-Ropero, Violeta Serra, Rehna Krishnan, Karim Mekhail, Razqallah Hakem, Jordi Bruna, Mary Helen Barcellos-Hoff, Francesc Viñals, Álvaro Aytes, Miquel Angel Pujana","doi":"10.1093/narcan/zcaf007","DOIUrl":"10.1093/narcan/zcaf007","url":null,"abstract":"<p><p>Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway that cancer cells deficient in homologous recombination rely on, making them vulnerable to synthetic lethality via inhibition of poly(ADP-ribose) polymerase (PARP). Targeting alt-EJ effector DNA polymerase theta (POLθ), which synergizes with PARP inhibitors and can overcome resistance, is of significant preclinical and clinical interest. However, the transcriptional regulation of alt-EJ and its interactions with processes driving cancer progression remain poorly understood. Here, we show that alt-EJ is suppressed by hypoxia while positively associated with MYC (myelocytomatosis oncogene) transcriptional activity. Hypoxia reduces <i>PARP1</i> and <i>POLQ</i> expression, decreases MYC binding at their promoters, and lowers PARylation and alt-EJ-mediated DNA repair in cancer cells. Tumors with <i>HIF1A</i> mutations overexpress the alt-EJ gene signature. Inhibition of hypoxia-inducible factor 1α or <i>HIF1A</i> expression depletion, combined with PARP or POLθ inhibition, synergistically reduces the colony-forming capacity of cancer cells. Deep learning reveals the anticorrelation between alt-EJ and hypoxia across regions in tumor images, and the predictions for these and MYC activity achieve area under the curve values between 0.70 and 0.86. These findings further highlight the critical role of hypoxia in modulating DNA repair and present a strategy for predicting and improving outcomes centered on targeting alt-EJ.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf007"},"PeriodicalIF":3.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11886861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IGF2BP1 oncogene is a druggable m⁶A-dependent enhancer of YAP1-driven gene expression in ovarian cancer.","authors":"Annekatrin Schott, Theresa Simon, Simon Müller, Alexander Rausch, Bianca Busch, Markus Glaß, Danny Misiak, Mohammad Dipto, Hend Elrewany, Lara Meret Peters, Sunita Tripathee, Ehab Ghazy, Florian Müller, Robin Benedikt Rolnik, Marcell Lederer, Ali Hmedat, Martina Vetter, Markus Wallwiener, Wolfgang Sippl, Stefan Hüttelmaier, Nadine Bley","doi":"10.1093/narcan/zcaf006","DOIUrl":"10.1093/narcan/zcaf006","url":null,"abstract":"<p><p>The Hippo/YAP1 signaling pathway regulates normal development by controlling contact inhibition of growth. In cancer, YAP1 activation is often dysregulated, leading to excessive tumor growth and metastasis. SRC kinase can cross talk to Hippo signaling by disrupting adherens junctions, repressing the Hippo cascade, or activating YAP1 to promote proliferation. Here, we demonstrate that the IGF2 messenger RNA-binding protein 1 (IGF2BP1) impedes the repression of YAP1 by Hippo signaling in carcinomas. IGF2BP1 stabilizes the YAP1 messenger RNA (mRNA) and enhances YAP1 protein synthesis through an m⁶A-dependent interaction with the 3' untranslated region of the YAP1 mRNA, thereby increasing YAP1/TAZ-driven transcription to bypass contact inhibition of tumor cell growth. Inhibiting IGF2BP1-mRNA binding using BTYNB reduces YAP1 levels and transcriptional activity, leading to significant growth inhibition in carcinoma cells and ovarian cancer organoids. In contrast, SRC inhibition with Saracatinib fails to inhibit YAP1/TAZ-driven transcription and cell growth in general. This is particularly significant in de-differentiated, rather mesenchymal carcinoma-derived cells, which exhibit high IGF2BP1 and YAP1 expression, rendering them less reliant on SRC-directed growth stimulation. In such invasive carcinoma models, the combined inhibition of SRC, IGF2BP1, and YAP1/TAZ proved superior over monotherapies. These findings highlight the therapeutic potential of targeting IGF2BP1, a key regulator of oncogenic transcription networks.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf006"},"PeriodicalIF":3.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vivo</i> selection of anti-glioblastoma DNA aptamers in an orthotopic patient-derived xenograft model.","authors":"Caroline D Doherty, Brandon A Wilbanks, Sonia Jain, Keenan S Pearson, Katie K Bakken, Danielle M Burgenske, Nay Won Lett, Jann N Sarkaria, Louis J Maher","doi":"10.1093/narcan/zcaf005","DOIUrl":"10.1093/narcan/zcaf005","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor of adults. Current therapeutic options yield dismal prognoses that have remained essentially unchanged over nearly two decades. Diffuse growth patterns, high intratumoral heterogeneity, and variable blood-brain barrier integrity limit treatment efficacy, creating challenges that rational small molecule design has not overcome. Antibody-drug conjugates have shown some promise, leading us to hypothesize that smaller folded DNA aptamers, developed <i>in vivo</i> via principles of natural selection, might eventually have advantages for drug delivery. Here, we document the first <i>in vivo</i> DNA aptamer selection involving an orthotopic patient-derived xenograft GBM mouse model to identify tumor-homing DNA aptamers. We demonstrate the preferential accumulation of these aptamers in the tumor relative to other tissues 4 h after intraperitoneal injection. The aptamers can be detected by quantitative polymerase chain reaction, fluorescent tumor staining, and stain GBM tumor section from untreated mice and the GBM tumor cells in culture. Two of three candidates are selective for the target cell line <i>in vitro</i> and do not bind other human tumor cells. <i>In vivo</i> selection of tumor-specific DNA aptamers demonstrates a novel approach for diagnostics or toxin delivery that might allow for the development of individualized therapies.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf005"},"PeriodicalIF":3.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapy enhancing chromosome instability may be advantageous for <i>IDH1</i> ^R132H/WT gliomas.","authors":"Nikolay V Goncharov, Ivan N Baklanov, Valeriia S Gulaia, Anastasiia P Shuliak, Daria V Lanskikh, Valeriia M Zhmenia, Mikhail E Shmelev, Nikita A Shved, Jing Wu, Mikhail Liskovykh, Vladimir Larionov, Natalay Kouprina, Vadim V Kumeiko","doi":"10.1093/narcan/zcaf003","DOIUrl":"10.1093/narcan/zcaf003","url":null,"abstract":"<p><p>Recently revised brain tumor classification suggested a glioma treatment strategy that takes into consideration molecular variants in <i>IDH1</i> and <i>TP53</i> marker genes. While pathogenic variants of IDH1 and TP53 can be accompanied by chromosomal instability (CIN), the impact of <i>IDH1</i> and <i>TP53</i> mutations on genome stability remains unstudied. Elevated CIN might provide therapeutic targets, based on synergistic effects of chemotherapy with CIN-inducing drugs. Using an assay based on human artificial chromosomes, we investigated the impact of common glioma missense mutations in <i>IDH1</i> and <i>TP53</i> on chromosome transmission and demonstrated that IDH1R132H and TP53R248Q variants elevate CIN. We next found enhanced CIN levels and the sensitivity of <i>IDH1</i> ^R132H/WT and <i>TP53</i> ^R248Q/R248Q genotypes, introduced into U87 MG glioma cells by CRISPR/Cas9, to different drugs, including conventional temozolomide. It was found that U87 MG cells carrying <i>IDH1</i> ^R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring <i>IDH1</i> ^R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the <i>IDH1</i> ^R132H/WT genotype could be advantageous for adjuvant treatment.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf003"},"PeriodicalIF":3.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of hydrazone-based G-quadruplex ligands on <i>FANCJ/BRIP1</i>-depleted cancer cells and a <i>Caenorhabditis elegans dog-1^-/-</i> strain.","authors":"Marcello Germoglio, Federica D'Aria, Giuseppe Cortone, Antonello Prodomo, Mohammad Mahtab, Rita Morigi, Jussara Amato, Francesca M Pisani, Concetta Giancola","doi":"10.1093/narcan/zcaf004","DOIUrl":"10.1093/narcan/zcaf004","url":null,"abstract":"<p><p>G-quadruplex (G4) DNAs are alternative nucleic acid structures, proposed to play important roles in regulating DNA replication, gene transcription, and translation. Several specialized DNA helicases are involved in cellular G4 metabolism, in some cases with redundant functions. Among them, human FANCJ/BRIP1, which has orthologs in all metazoans, is one of the most powerful G4 resolvases, believed to act mainly at DNA replication forks. Here, we tested the effects of a set of hydrazone-derivative G4 ligands in a <i>FANCJ</i>-knocked-out HeLa cell line and in a <i>Caenorhabditis elegans</i> strain, where DOG-1, a FANCJ ortholog, was disrupted, as a whole organism model system. Our results revealed that loss of FANCJ specifically sensitized cancer cells to FIM-15, a mono-guanylhydrazone derivative bearing the diimidazopyrimidine core, among the tested hydrazone-based compounds and induced enhanced DNA damage in different chromosomal sites including telomeric ends. Moreover, dietary administration of FIM-15 to <i>dog-1</i> ^-/- nematodes stabilized G4 structures in gonadal cell nuclei and resulted in compromised embryonic development in the first-generation post-treatment. Collectively, our findings unveil a specific vulnerability of <i>FANCJ</i>-knocked-out cancer cells (and DOG-1-lacking worms) to G4 stabilization by the FIM-15 compound. This study provides an important proof-of-principle for use of G4 ligands in synthetic lethality-based therapeutic approaches targeting FANCJ-defective cancer cells.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf004"},"PeriodicalIF":3.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone H3E50K remodels chromatin to confer oncogenic activity and support an EMT phenotype.","authors":"Kirti Sad, Dorelle V Fawwal, Celina Y Jones, Emily J Hill, Katie T Skinner, Miranda L Adams, Severin Lustenberger, Richard S Lee, Sandhya V Lohano, Satvik R Elayavalli, Jonathan Farhi, Christina C Mehta, Laramie D Lemon, Milo B Fasken, Andrew L Hong, Steven A Sloan, Anita H Corbett, Jennifer M Spangle","doi":"10.1093/narcan/zcaf002","DOIUrl":"10.1093/narcan/zcaf002","url":null,"abstract":"<p><p>Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring <i>BRAF</i> mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial-to-mesenchymal transition. Functional studies using <i>Saccharomyces cerevisiae</i> reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf002"},"PeriodicalIF":3.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}