NAR cancerPub Date : 2025-08-07eCollection Date: 2025-09-01DOI: 10.1093/narcan/zcaf023
Tzofit Elbaz Biton, Michal Feldman, Tomer Davidy, Nili Tickotsky Moskovitz, Liron Levin, Daniel Sevilla, Colin R Goding, Emily Bernstein, Dan Levy
{"title":"SETD6 mediates selective interaction and genomic occupancy of BRD4 and MITF in melanoma cells.","authors":"Tzofit Elbaz Biton, Michal Feldman, Tomer Davidy, Nili Tickotsky Moskovitz, Liron Levin, Daniel Sevilla, Colin R Goding, Emily Bernstein, Dan Levy","doi":"10.1093/narcan/zcaf023","DOIUrl":"10.1093/narcan/zcaf023","url":null,"abstract":"<p><p>Aberrant transcriptional programs mediate malignant transformation of melanoma, the most aggressive form of skin cancer. The lysine methyltransferase SETD6 has been implicated in regulating transcription, cell adhesion, migration, and other processes in various cancers; however its role in melanoma remains unexplored. We recently reported that SETD6 monomethylates the BRD4 at K99 to selectively regulate transcription of genes involved in mRNA (messenger RNA) translation. Here, we observed that BRD4 methylation at K99 by SETD6 occurs in melanoma cells. Knockout of SETD6 or a point mutation at BRD4-K99 disrupts BRD4 genomic occupancy. In addition, we show that SETD6 interacts with MITF, a master transcription factor in melanocytes and melanoma, and influences the genomic distribution of MITF. Mechanistically, we uncover a novel chromatin-localized interaction between BRD4 and MITF in melanoma. Our data suggest that BRD4 binds MITF in melanoma cells and that this interaction is dependent on both SETD6-mediated methylation of BRD4 and MITF acetylation. This chromatin complex plays a pivotal role in selective recruitment of BRD4 and MITF to different genomic loci in melanoma cells.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 3","pages":"zcaf023"},"PeriodicalIF":3.2,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850228","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}
NAR cancerPub Date : 2025-06-18eCollection Date: 2025-06-01DOI: 10.1093/narcan/zcaf020
Anne-Laure Vitte, Florent Chuffart, Emmanuelle Jacquet, Eleni Nika, Mireille Mousseau, Ina Jung, Séverine Tabone-Eglinger, Thomas Bachelot, Sophie Rousseaux, Saadi Khochbin, Ekaterina Bourova-Flin
{"title":"Discovery of epigenetically silenced tumour suppressor genes in aggressive breast cancer through a computational approach.","authors":"Anne-Laure Vitte, Florent Chuffart, Emmanuelle Jacquet, Eleni Nika, Mireille Mousseau, Ina Jung, Séverine Tabone-Eglinger, Thomas Bachelot, Sophie Rousseaux, Saadi Khochbin, Ekaterina Bourova-Flin","doi":"10.1093/narcan/zcaf020","DOIUrl":"10.1093/narcan/zcaf020","url":null,"abstract":"<p><p>Breast cancer is characterized by genetic and epigenetic deregulations, leading to aberrant expression of tissue-specific genes that are normally silent in healthy breast tissue. Our previous work identified the embryonic stem cell-specific gene <i>DNMT3B</i>, a <i>de novo</i> DNA methyltransferase, as aberrantly activated in breast cancer, correlating with aggressive tumour behaviour and high relapse risk, regardless of molecular subtype. Through integrative bioinformatic analyses of DNA methylation and transcriptomic data, we identified 154 genes downregulated via <i>DNMT3B</i>-driven promoter hypermethylation, many of which are associated with high relapse risk. Notably, the tumour suppressor gene <i>GATA3</i> emerged as a primary target of functional inactivation through either loss-of-function mutations or <i>DNMT3B</i>-controlled hypermethylation, in a mutually exclusive manner. Both mechanisms of <i>GATA3</i> inactivation were associated with similar molecular signatures linked to tumour progression, increased malignancy, and poorer prognosis. However, distinct differences were observed, with immune- and inflammation-related genes enriched in <i>GATA3</i> hypermethylation cases but depleted in mutation-driven silencing. Additionally, our analysis uncovered other potential tumour suppressor genes epigenetically repressed in aggressive breast cancers. These findings underscore a broader role of <i>GATA3</i> inactivation beyond genetic alterations and suggest therapeutic opportunities to target epigenetically silenced tumour suppressors in aggressive breast tumours.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf020"},"PeriodicalIF":3.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532089","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}
NAR cancerPub Date : 2025-05-27eCollection Date: 2025-06-01DOI: 10.1093/narcan/zcaf018
Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng
{"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}
NAR cancerPub Date : 2025-05-05eCollection Date: 2025-06-01DOI: 10.1093/narcan/zcaf017
Huanzhou Xu, Tarun E Hutchinson, Siva Koganti, Beth A Rousseau, Daniel Xia, Michael T McIntosh, Sumita Bhaduri-McIntosh
{"title":"Leveraging the interconnected unfolded protein response and NLRP3 inflammasome pathways to reactivate Epstein-Barr virus in diffuse large B-cell lymphomas.","authors":"Huanzhou Xu, Tarun E Hutchinson, Siva Koganti, Beth A Rousseau, Daniel Xia, Michael T McIntosh, Sumita Bhaduri-McIntosh","doi":"10.1093/narcan/zcaf017","DOIUrl":"10.1093/narcan/zcaf017","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL), when associated with Epstein-Barr virus (EBV) in immunocompromised individuals such as AIDS patients, presents a significant treatment challenge. Lytic induction therapy, which reactivates latent EBV to directly kill tumor cells and sensitize them to nucleoside analogs that block viral replication and immune clearance, offers promise. However, little is known about EBV reactivation in DLBCL. Here, we examined four EBV-positive DLBCL cell lines and found variable, cell-line-specific responses to lytic stimuli, with most showing an abortive response-either before or after genome replication, without virus release. This is in contrast to commonly studied lymphoma cells in which EBV reactivation typically leads to a full lytic cycle. Mechanistically, we show that the unfolded protein response (UPR), via a splice variant of the transcription factor XBP1, upregulates TXNIP and NLRP3, activating the inflammasome and removing a barrier to transcription of the EBV latent-to-lytic switch gene <i>BZLF1</i>. Combining lytic induction with the nucleoside analog ganciclovir enhanced oncolytic cell death. This study identifies a pivotal link between two danger sensing pathways, the UPR and the inflammasome, in reactivating the virus resident in DLBCL and suggests that controlled lytic reactivation could provide a basis for EBV-targeted therapies to improve outcomes in this malignancy.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf017"},"PeriodicalIF":3.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046727","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}
NAR cancerPub Date : 2025-04-23eCollection Date: 2025-06-01DOI: 10.1093/narcan/zcaf015
Kaveri Goel, Vani Venkatappa, Kimiko L Krieger, Dongquan Chen, Arun Sreekumar, Natalie R Gassman
{"title":"PARP inhibitor response is enhanced in prostate cancer when XRCC1 expression is reduced.","authors":"Kaveri Goel, Vani Venkatappa, Kimiko L Krieger, Dongquan Chen, Arun Sreekumar, Natalie R Gassman","doi":"10.1093/narcan/zcaf015","DOIUrl":"10.1093/narcan/zcaf015","url":null,"abstract":"<p><p>Prostate cancer (PCa) is the second most common cancer worldwide and the fifth leading cause of cancer-related deaths among men. The emergence of metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) exemplifies the complex disease management for PCa. PARP inhibitors (PARPis) are being tested to treat mCRPC in tumors with defective homologous recombination repair (HRR) to address this complexity. However, increasing resistance towards PARPi in HRR-deficient patients and the low percentage of HRR-defective mCRPC patients requires the identification of new genes whose deficiency can be exploited for PARPi treatment. XRCC1 is a DNA repair protein critical in the base excision repair (BER) and single strand break repair (SSBR) pathways. We analyzed PCa patients' cohorts and found that XRCC1 expression varies widely, with many patients showing low XRCC1 expression. We created XRCC1 deficiency in PCa models to examine PARPi sensitivity. XRCC1 loss conferred hypersensitivity to PARPi by promoting the accumulation of DNA double-strand breaks, increasing cell-cycle arrest, and inducing apoptosis. We confirmed that XRCC1 expression correlated with PARPi sensitivity using a doxycycline-inducible system. Therefore, we conclude that XRCC1 expression level predicts response to PARPi, and the clinical utility of PARPi in PCa can extend to low XRCC1 expressing tumors.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf015"},"PeriodicalIF":3.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055870","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}
NAR cancerPub Date : 2025-04-23eCollection Date: 2025-06-01DOI: 10.1093/narcan/zcaf014
Oliver Artz, James R White, Benoit Rousseau, Guillem Argiles, Michael B Foote, Paul Johannet, Miteshkumar Patel, Somer Abdelfattah, Shrey Patel, Callahan Wilde, David Mieles, Luis A Diaz
{"title":"The role of recurrent somatic mutations that alter conserved m<sup>6</sup>A motifs in human cancer.","authors":"Oliver Artz, James R White, Benoit Rousseau, Guillem Argiles, Michael B Foote, Paul Johannet, Miteshkumar Patel, Somer Abdelfattah, Shrey Patel, Callahan Wilde, David Mieles, Luis A Diaz","doi":"10.1093/narcan/zcaf014","DOIUrl":"10.1093/narcan/zcaf014","url":null,"abstract":"<p><p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is the most abundant internal RNA modification in eukaryotes and plays a key role in cellular growth and development. Global changes in cellular methylated RNA and m<sup>6</sup>A-mediated transcript regulation significantly impact oncogenesis. Here, we investigate how recurrent synonymous and non-synonymous somatic mutations abolishing individual canonical methylated m<sup>6</sup>A motifs affect transcript levels and survival of patients with cancer. Moreover, we explore the effect of these mutations on creating <i>de novo</i> m<sup>6</sup>A motifs. To this end, we compared publicly available data on m<sup>6</sup>A sites with mutations reported in The Cancer Genome Atlas (TCGA). We find that mutations disrupting or creating m<sup>6</sup>A motifs display a low recurrence and have a negligible impact on RNA abundance. Patients with the highest number of disrupted m<sup>6</sup>A sites or newly generated m<sup>6</sup>A motifs did not generally exhibit alterations in mortality risk or outcomes. Hence, our data suggest that mutational alterations in the m<sup>6</sup>A motif landscape are unlikely to be a primary mechanism for regulating gene function across most cancer types. This may be attributed to the fact that mutations typically affect individual m<sup>6</sup>A sites, which is likely insufficient to significantly impact gene expression.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf014"},"PeriodicalIF":3.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048696","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}
NAR cancerPub Date : 2025-03-20eCollection Date: 2025-03-01DOI: 10.1093/narcan/zcaf009
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
{"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<sup>G12V</sup>-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<sup>G12V</sup>-expressing cells. TRIP13 promotes survival of KRAS<sup>G12V</sup>-expressing HPNE cells in a homologous recombination (HR)-dependent manner. KRAS<sup>G12V</sup>-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}
NAR cancerPub Date : 2025-03-07eCollection Date: 2025-03-01DOI: 10.1093/narcan/zcaf007
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
{"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}