NAR cancer最新文献

{"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":"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":"Spatial transcriptomics in breast cancer reveals tumour microenvironment-driven drug responses and clonal therapeutic heterogeneity.","authors":"María José Jiménez-Santos, Santiago García-Martín, Marcos Rubio-Fernández, Gonzalo Gómez-López, Fátima Al-Shahrour","doi":"10.1093/narcan/zcae046","DOIUrl":"10.1093/narcan/zcae046","url":null,"abstract":"<p><p>Breast cancer patients are categorized into three subtypes with distinct treatment approaches. Precision oncology has increased patient outcomes by targeting the specific molecular alterations of tumours, yet challenges remain. Treatment failure persists due to the coexistence of several malignant subpopulations with different drug sensitivities within the same tumour, a phenomenon known as intratumour heterogeneity (ITH). This heterogeneity has been extensively studied from a tumour-centric view, but recent insights underscore the role of the tumour microenvironment in treatment response. Our research utilizes spatial transcriptomics data from breast cancer patients to predict drug sensitivity. We observe diverse response patterns across tumour, interphase and microenvironment regions, unveiling a sensitivity and functional gradient from the tumour core to the periphery. Moreover, we find tumour therapeutic clusters with different drug responses associated with distinct biological functions driven by unique ligand-receptor interactions. Importantly, we identify genetically identical subclones with different responses depending on their location within the tumour ducts. This research underscores the significance of considering the distance from the tumour core and microenvironment composition when identifying suitable treatments to target ITH. Our findings provide critical insights into optimizing therapeutic strategies, highlighting the necessity of a comprehensive understanding of tumour biology for effective cancer treatment.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae046"},"PeriodicalIF":3.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866848","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":"RAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer patient-derived xenograft models.","authors":"Francien Talens, Vivian Oliviera Nunes Teixeira, Yannick P Kok, Mengting Chen, Efraim H Rosenberg, Rashmie Debipersad, Evelien W Duiker, Nathalie van den Tempel, Marketa Janatova, Petra Zemankova, Petra M Nederlof, G Bea A Wisman, Zdenek Kleibl, Steven de Jong, Marcel A T M van Vugt","doi":"10.1093/narcan/zcae044","DOIUrl":"10.1093/narcan/zcae044","url":null,"abstract":"<p><p>Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat <i>BRCA1/2</i> mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection. Analysis of <i>BRCA1/2</i> status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a <i>BRCA1/2</i> alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. <i>In vivo</i>, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using <i>ex vivo</i> irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without <i>BRCA1/2</i> alterations. In contrast, replication fork protection or replication speed in <i>ex vivo</i> tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking <i>BRCA1/2</i> alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that <i>ex vivo</i> RAD51 analysis effectively predicts <i>in vivo</i> olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae044"},"PeriodicalIF":3.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11604054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752753","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":"Massively parallel reporter assays identify enhancer elements in oesophageal Adenocarcinoma.","authors":"Shen-Hsi Yang, Ibrahim Ahmed, Yaoyong Li, Christopher W Bleaney, Andrew D Sharrocks","doi":"10.1093/narcan/zcae041","DOIUrl":"10.1093/narcan/zcae041","url":null,"abstract":"<p><p>Cancer is a disease underpinned by aberrant gene expression. Enhancers are regulatory elements that play a major role in transcriptional control and changes in active enhancer function are likely critical in the pathogenesis of oesophageal adenocarcinoma (OAC). Here, we utilise STARR-seq to profile the genome-wide enhancer landscape in OAC and identify hundreds of high-confidence enhancer elements. These regions are enriched in enhancer-associated chromatin marks, are actively transcribed and exhibit high levels of associated gene activity in OAC cells. These characteristics are maintained in human patient samples, demonstrating their disease relevance. This relevance is further underlined by their responsiveness to oncogenic ERBB2 inhibition and increased activity compared to the pre-cancerous Barrett's state. Mechanistically, these enhancers are linked to the core OAC transcriptional network and in particular KLF5 binding is associated with high level activity, providing further support for a role of this transcription factor in defining the OAC transcriptome. Our results therefore uncover a set of enhancer elements with physiological significance, that widen our understanding of the molecular alterations in OAC and point to mechanisms through which response to targeted therapy may occur.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 4","pages":"zcae041"},"PeriodicalIF":3.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484580","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":"Decoding the molecular symphony: interactions between the m⁶A and p53 signaling pathways in cancer.","authors":"Rachel Shoemaker, Mo-Fan Huang, Ying-Si Wu, Cheng-Shuo Huang, Dung-Fang Lee","doi":"10.1093/narcan/zcae037","DOIUrl":"10.1093/narcan/zcae037","url":null,"abstract":"<p><p>The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant gene transcription, activation of oncogenic signaling and cancer development. Although mutations can occur at any point in the genetic sequence, missense mutations comprise the majority of observed p53 mutations in cancers regardless of whether the mutation is germline or somatic. One biological process involved in both mutant and wild-type p53 signaling is the <i>N</i> ⁶-methyladenosine (m⁶A) epitranscriptomic network, a type of post-transcriptional modification involved in over half of all eukaryotic mRNAs. Recently, a significant number of findings have demonstrated unique interactions between p53 and the m⁶A epitranscriptomic network in a variety of cancer types, shedding light on a previously uncharacterized connection that causes significant dysregulation. Cross-talk between wild-type or mutant p53 and the m⁶A readers, writers and erasers has been shown to impact cellular function and induce cancer formation by influencing various cancer hallmarks. Here, this review aims to summarize the complex interplay between the m⁶A epitranscriptome and p53 signaling pathway, highlighting its effects on tumorigenesis and other hallmarks of cancer, as well as identifying its therapeutic implications for the future.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 3","pages":"zcae037"},"PeriodicalIF":3.4,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335463","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}