NAR cancer最新文献_第7页

GSK-3484862, a DNMT1 degrader, promotes DNMT3B expression in lung cancer cells. GSK-3484862是一种DNMT1降解剂，可促进肺癌细胞中DNMT3B的表达。

IF 4.6

NAR cancer Pub Date : 2025-05-27 eCollection Date: 2025-06-01 DOI: 10.1093/narcan/zcaf018

Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng

{"title":"GSK-3484862, a DNMT1 degrader, promotes DNMT3B expression in lung cancer cells.","authors":"Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng","doi":"10.1093/narcan/zcaf018","DOIUrl":"10.1093/narcan/zcaf018","url":null,"abstract":"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 DNMT3B expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting DNMT3B in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces demethylation at DNMT3B regulatory elements including a candidate enhancer located ∼10 kb upstream of the DNMT3B transcription start site, as well as at the promoter of TERT (telomerase reverse transcriptase), a potential activator of DNMT3B expression. These demethylation events correlate with upregulation of DNMT3B expression. These findings suggest that combining inhibitors targeting DNMT1, the maintenance methyltransferase, with those targeting DNMT3A/3B, the de novo methyltransferases, or using pan-DNMT inhibitors, could enhance anticancer efficacy and reduce resistance.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf018"},"PeriodicalIF":4.6,"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}

引用次数: 0

Correction to 'PDXNet portal: patient-derived Xenograft model, data, workflow and tool discovery'. 更正“PDXNet门户：患者衍生异种移植模型，数据，工作流程和工具发现”。

IF 4.6

NAR cancer Pub Date : 2025-05-27 eCollection Date: 2025-06-01 DOI: 10.1093/narcan/zcaf019

引用次数: 0

A systematic evaluation of the therapeutic potential of endogenous-ADAR editors in cancer prevention and treatment. 系统评价内源性adar编辑器在癌症预防和治疗中的治疗潜力。

IF 4.6

NAR cancer Pub Date : 2025-05-06 eCollection Date: 2025-06-01 DOI: 10.1093/narcan/zcaf016

Rona Merdler-Rabinowicz, Ariel Dadush, Sumeet Patiyal, Padma Sheila Rajagopal, Gulzar N Daya, Shay Ben-Aroya, Alejandro A Schäffer, Eli Eisenberg, Eytan Ruppin, Erez Y Levanon

{"title":"A systematic evaluation of the therapeutic potential of endogenous-ADAR editors in cancer prevention and treatment.","authors":"Rona Merdler-Rabinowicz, Ariel Dadush, Sumeet Patiyal, Padma Sheila Rajagopal, Gulzar N Daya, Shay Ben-Aroya, Alejandro A Schäffer, Eli Eisenberg, Eytan Ruppin, Erez Y Levanon","doi":"10.1093/narcan/zcaf016","DOIUrl":"10.1093/narcan/zcaf016","url":null,"abstract":"Adenosine deaminases acting on RNA (ADAR) enzymes constitute a natural cellular mechanism that induces A-to-I(G) editing, introducing genetic changes at the RNA level. Recently, interest in the endogenous-ADAR editor has emerged for correcting genetic mutations, consisting of a programmed oligonucleotide that attracts the native ADAR, thereby offering opportunities for medical therapy. Here, we systematically chart the scope of cancer mutations that endogenous-ADAR can correct. First, analyzing germline single nucleotide variants in cancer predisposition genes, we find that endogenous-ADAR can revert a fifth of them, reducing the risk of cancer development later in life. Second, examining somatic mutations across various cancer types, we find that it has the potential to correct at least one driver mutation in over a third of the samples, suggesting a promising future treatment strategy. We also highlight key driver mutations that are amenable to endogenous-ADAR, and are thus of special clinical interest. As using endogenous-ADAR entails delivering relatively small payloads, the prospects of delivering endogenous-ADAR to various cancers seem promising. We expect that the large scope of correctable mutations that are systematically charted here for the first time will pave the way for a new era of cancer treatment options.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf016"},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050677","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}

引用次数: 0

Leveraging the interconnected unfolded protein response and NLRP3 inflammasome pathways to reactivate Epstein-Barr virus in diffuse large B-cell lymphomas. 利用相互关联的未折叠蛋白反应和NLRP3炎性小体途径在弥漫性大b细胞淋巴瘤中重新激活eb病毒

IF 4.6

NAR cancer Pub Date : 2025-05-05 eCollection Date: 2025-06-01 DOI: 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":"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 BZLF1. 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.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf017"},"PeriodicalIF":4.6,"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}

引用次数: 0

Synergistic enhancement of PARP inhibition via small molecule UNI66-mediated suppression of BRD4-dependent transcription of RAD51 and CtIP. 通过小分子uni66介导的RAD51和CtIP brd4依赖性转录抑制协同增强PARP抑制作用。

IF 4.6

NAR cancer Pub Date : 2025-04-30 eCollection Date: 2025-06-01 DOI: 10.1093/narcan/zcaf013

Enkhzul Amarsanaa, Minwoo Wie, Unbeom Shin, Nabeela Bilal, Jungme Hwang, Eun A Lee, Seon Young Lee, Byung-Gyu Kim, Shinseog Kim, Yoonsung Lee, Kyungjae Myung

{"title":"Synergistic enhancement of PARP inhibition via small molecule UNI66-mediated suppression of BRD4-dependent transcription of RAD51 and CtIP.","authors":"Enkhzul Amarsanaa, Minwoo Wie, Unbeom Shin, Nabeela Bilal, Jungme Hwang, Eun A Lee, Seon Young Lee, Byung-Gyu Kim, Shinseog Kim, Yoonsung Lee, Kyungjae Myung","doi":"10.1093/narcan/zcaf013","DOIUrl":"10.1093/narcan/zcaf013","url":null,"abstract":"Targeted therapy leveraging synthetic lethality in homologous recombination (HR)-defective tumors, particularly in BRCA-mutated tumors through poly(ADP-ribose) polymerase (PARP)-dependent repair inhibition, has shown success. However, the challenge lies in the ability of the tumors to reactivate HR via diverse mechanisms, leading to resistance against PARP-dependent repair inhibition. Addressing this issue, the down-regulation of HR activity has been explored as a potential strategy to overcome PARP inhibitor-resistant tumors. Yet, the intricate modulation of HR gene expression in mammalian cells is still not fully understood. In this study, we used a small molecule, UNI66, identified from high-throughput screening, to investigate regulatory mechanisms of HR. UNI66 was observed to induce synthetic lethality in PARP1-deficient cells and enhanced the sensitivity of multiple cancer cells to PARP inhibitors, suggesting a role in HR down-regulation. Mechanistically, UNI66 was found to interact with and inhibit BRD4 protein binding to the promoters of CtIP and RAD51 genes, resulting in the down-regulation of their transcription. This decrease in CtIP and RAD51 expression was associated with reduced HR activity, thereby increasing the sensitivity of tumors to PARP inhibitors. These findings indicate that BRD4-mediated transcriptional regulation of CtIP and RAD51 influences HR activity, which may have implications for overcoming resistance to PARP inhibitors.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf013"},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048483","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}

引用次数: 0

PARP inhibitor response is enhanced in prostate cancer when XRCC1 expression is reduced. 当XRCC1表达降低时，前列腺癌中PARP抑制剂反应增强。

IF 4.6

NAR cancer Pub Date : 2025-04-23 eCollection Date: 2025-06-01 DOI: 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":"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.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf015"},"PeriodicalIF":4.6,"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}

引用次数: 0

The role of recurrent somatic mutations that alter conserved m⁶A motifs in human cancer. 复发性体细胞突变改变保守的m6A基序在人类癌症中的作用。

IF 4.6

NAR cancer Pub Date : 2025-04-23 eCollection Date: 2025-06-01 DOI: 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 m6A 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":"N6-methyladenosine (m6A) 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 m6A-mediated transcript regulation significantly impact oncogenesis. Here, we investigate how recurrent synonymous and non-synonymous somatic mutations abolishing individual canonical methylated m6A motifs affect transcript levels and survival of patients with cancer. Moreover, we explore the effect of these mutations on creating de novo m6A motifs. To this end, we compared publicly available data on m6A sites with mutations reported in The Cancer Genome Atlas (TCGA). We find that mutations disrupting or creating m6A motifs display a low recurrence and have a negligible impact on RNA abundance. Patients with the highest number of disrupted m6A sites or newly generated m6A motifs did not generally exhibit alterations in mortality risk or outcomes. Hence, our data suggest that mutational alterations in the m6A 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 m6A sites, which is likely insufficient to significantly impact gene expression.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf014"},"PeriodicalIF":4.6,"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}

引用次数: 0

Identification of FLYWCH1 as a regulator of platinum-resistance in epithelial ovarian cancer. 确定 FLYWCH1 是上皮性卵巢癌铂类抗药性的调节因子。

IF 4.6

NAR cancer Pub Date : 2025-04-04 eCollection Date: 2025-06-01 DOI: 10.1093/narcan/zcaf012

Tabea L Fullstone, Helene Rohm, Till Kaltofen, Sophia Hierlmayer, Juliane Reichenbach, Simon Schweikert, Franziska Knodel, Ann-Kathrin Loeffler, Doris Mayr, Udo Jeschke, Sven Mahner, Mirjana Kessler, Fabian Trillsch, Philipp Rathert

{"title":"Identification of FLYWCH1 as a regulator of platinum-resistance in epithelial ovarian cancer.","authors":"Tabea L Fullstone, Helene Rohm, Till Kaltofen, Sophia Hierlmayer, Juliane Reichenbach, Simon Schweikert, Franziska Knodel, Ann-Kathrin Loeffler, Doris Mayr, Udo Jeschke, Sven Mahner, Mirjana Kessler, Fabian Trillsch, Philipp Rathert","doi":"10.1093/narcan/zcaf012","DOIUrl":"10.1093/narcan/zcaf012","url":null,"abstract":"Platinum-based combination chemotherapy remains the backbone of first-line treatment for patients with advanced epithelial ovarian cancer (EOC). While most patients initially respond well to the treatment, patients with relapse ultimately develop platinum resistance. This study identified FLYWCH-type zinc finger-containing protein 1 (FLYWCH1) as an important regulator in the resistance development process. We showed that the loss of FLYWCH1 promotes platinum resistance in EOC cells, and the low FLYWCH1 expression is correlated with poor prognosis of EOC patients. In platinum-sensitive cells, FLYWCH1 colocalizes with H3K9me3, but this association is significantly reduced when cells acquire resistance. The suppression of FLYWCH1 induces gene expression changes resulting in the deregulation of pathways associated with resistance. In line with its connection to H3K9me3, FLYWCH1 induces gene silencing in a synthetic reporter assay and the suppression of FLYWCH1 alters H3K9me3 at promoter regions and repeat elements. The loss of FLYWCH1 leads to the derepression of LTR and Alu repeats, thereby increasing transcriptional plasticity and driving the resistance development process. Our data highlight the importance of FLYWCH1 in chromatin biology and acquisition of platinum resistance through transcriptional plasticity and propose FLYWCH1 as a potential biomarker for predicting treatment responses in EOC patients.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf012"},"PeriodicalIF":4.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797536","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}

引用次数: 0

SRSF2 overexpression induces transcription-/replication-dependent DNA double-strand breaks and interferes with DNA repair pathways to promote lung tumor progression. SRSF2过表达会诱导转录/复制依赖性DNA双链断裂，干扰DNA修复途径，从而促进肺部肿瘤的进展。

IF 4.6

NAR cancer Pub Date : 2025-04-02 eCollection Date: 2025-06-01 DOI: 10.1093/narcan/zcaf011

Manal Khalife, Tao Jia, Pierre Caron, Amani Shreim, Aurelie Genoux, Agnese Cristini, Amelie Pucciarelli, Marie Leverve, Nina Lepeltier, Néstor García-Rodríguez, Fabien Dalonneau, Shaliny Ramachandran, Lara Fernandez Martinez, Guillaume Marcion, Nicolas Lemaitre, Elisabeth Brambilla, Carmen Garrido, Ester M Hammond, Pablo Huertas, Sylvie Gazzeri, Olivier Sordet, Beatrice Eymin

{"title":"SRSF2 overexpression induces transcription-/replication-dependent DNA double-strand breaks and interferes with DNA repair pathways to promote lung tumor progression.","authors":"Manal Khalife, Tao Jia, Pierre Caron, Amani Shreim, Aurelie Genoux, Agnese Cristini, Amelie Pucciarelli, Marie Leverve, Nina Lepeltier, Néstor García-Rodríguez, Fabien Dalonneau, Shaliny Ramachandran, Lara Fernandez Martinez, Guillaume Marcion, Nicolas Lemaitre, Elisabeth Brambilla, Carmen Garrido, Ester M Hammond, Pablo Huertas, Sylvie Gazzeri, Olivier Sordet, Beatrice Eymin","doi":"10.1093/narcan/zcaf011","DOIUrl":"10.1093/narcan/zcaf011","url":null,"abstract":"SRSF2 (serine/arginine-rich splicing factor 2) is a critical regulator of pre-messenger RNA splicing, which also plays noncanonical functions in transcription initiation and elongation. Although elevated levels of SRSF2 are associated with advanced stages of lung adenocarcinoma (LUAD), the mechanisms connecting SRSF2 to lung tumor progression remain unknown. We show that SRSF2 overexpression increases global transcription and replicative stress in LUAD cells, which correlates with the production of DNA damage, notably double-strand breaks (DSBs), likely resulting from conflicts between transcription and replication. Moreover, SRSF2 regulates DNA repair pathways by promoting homologous recombination and inhibiting nonhomologous end joining. Mechanistically, SRSF2 interacts with and enhances MRE11 (meiotic recombination 11) recruitment to chromatin, while downregulating 53BP1 messenger RNA and protein levels. Both events are likely contributing to SRSF2-mediated DNA repair process rerouting. Lastly, we show that SRSF2 and MRE11 expression is commonly elevated in LUAD and predicts poor outcome of patients. Altogether, our results identify a mechanism by which SRSF2 overexpression promotes lung cancer progression through a fine control of both DSB production and repair. Finally, we show that SRSF2 knockdown impairs late repair of ionizing radiation-induced DSBs, suggesting a more global function of SRSF2 in DSB repair by homologous recombination.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 2","pages":"zcaf011"},"PeriodicalIF":4.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782201","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}

引用次数: 0

Matrix stiffness modulates androgen response genes and chromatin state in prostate cancer. 前列腺癌中基质硬度调节雄激素反应基因和染色质状态。

IF 4.6

NAR cancer Pub Date : 2025-03-20 eCollection Date: 2025-03-01 DOI: 10.1093/narcan/zcaf010

Roosa Kaarijärvi, Heidi Kaljunen, Onni Niemi, Merja Räsänen, Ville Paakinaho, Kirsi Ketola

{"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":"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.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 1","pages":"zcaf010"},"PeriodicalIF":4.6,"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}

引用次数: 0