Molecular Oncology最新文献

Tumour-proximal deep serum proteomics identifies biomarkers associated with ovarian cancer. 肿瘤-近端深层血清蛋白质组学鉴定与卵巢癌相关的生物标志物。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-17 DOI: 10.1002/1878-0261.70351

Darren Lau, Daniel Pincher, Clifford Young, Nicholas Chappell, Noor A Lokman, Parul Mittal, Leigh Donnellan, Martin K Oehler, Doug A Brooks, Peter Hoffmann

{"title":"Tumour-proximal deep serum proteomics identifies biomarkers associated with ovarian cancer.","authors":"Darren Lau, Daniel Pincher, Clifford Young, Nicholas Chappell, Noor A Lokman, Parul Mittal, Leigh Donnellan, Martin K Oehler, Doug A Brooks, Peter Hoffmann","doi":"10.1002/1878-0261.70351","DOIUrl":"10.1002/1878-0261.70351","url":null,"abstract":"Ovarian cancer diagnosis is often delayed due to poorly defined clinical symptoms, underscoring the need for novel biomarkers that enable earlier detection. Protein biomarker discovery in blood samples is analytically challenging using mass spectrometry, as high-abundance proteins can obscure detection of low-abundance biomarkers. Ovarian vein (ovarian) and median cubital vein (peripheral) serum were collected from healthy women or patients with benign or malignant (majority stage I) serous ovarian tumours. Proteograph XT assay was employed as a protein enrichment methodology prior to LC-MS/MS analyses to obtain deeper proteome coverage in these samples. From an initial cohort of 53 samples, we identified 6603 proteins across all samples, including 3467 proteins uniquely identified in ovarian serum. Following exclusion of red blood cell-contaminated samples, differential abundance analysis identified 86 and 101 malignancy-associated protein candidates in ovarian and peripheral samples, respectively. Notably, ANK1, CAND1 and GMPR2 were differentially abundant across both sample types. Using logistic regression with repeated cross-validation and permutation testing, ANK1 demonstrated strong discriminatory performance [area under the curve (AUC) = 0.97] when combined with clinical CA125 measurements. These findings highlight the importance of ovarian vein sampling for enhanced access to tumour-associated proteins and support further validation of these candidate biomarkers for early ovarian cancer detection.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reprogramming tumor cells with LCOR mRNA nanotherapy to enhance immunotherapy. 用LCOR mRNA纳米疗法重编程肿瘤细胞以增强免疫治疗。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-15 DOI: 10.1002/1878-0261.70344

Gabriel Serra-Mir, Elena Haro-Martínez, Sandra Blasco-Benito, Chiara Cannatà, José Ángel Palomeque, Anna López-Plana, Maria Sanz-Flores, Marc Sabartés, Cristina Fornaguera, Toni Celià-Terrassa

{"title":"Reprogramming tumor cells with LCOR mRNA nanotherapy to enhance immunotherapy.","authors":"Gabriel Serra-Mir, Elena Haro-Martínez, Sandra Blasco-Benito, Chiara Cannatà, José Ángel Palomeque, Anna López-Plana, Maria Sanz-Flores, Marc Sabartés, Cristina Fornaguera, Toni Celià-Terrassa","doi":"10.1002/1878-0261.70344","DOIUrl":"10.1002/1878-0261.70344","url":null,"abstract":"Transcription factors (TFs) are often considered undruggable due to their structural complexity. mRNA technologies can overcome this therapeutic limitation by enabling dynamic protein replacement therapies. Here, we explore the TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth, at least in part by inducing the antigen presentation machinery (APM) in tumor cells and constraining cellular plasticity. These effects facilitate tumor immune recognition and immune-mediated tumor eradication. We used poly β-(amino esters) (pBAE) nanoparticles (NPs) for local delivery of Lcor mRNA in multiple breast cancer models. pBAE-NPs efficiently encapsulate mRNA and facilitate cellular uptake, achieving optimal endosomal escape, resulting in high transfection efficiency in vitro and in vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical models, intratumoral delivery of Lcor mRNA reduced tumor growth. Importantly, the combination of Lcor mRNA-loaded RH-pBAE-NPs with anti-PDL1 or anti-CTLA4 immunotherapies eradicated most of the tumors in our preclinical TNBC model. Overall, our nanotherapeutic strategy emerges as an innovative TF-replacement therapy in a lock-in/wipe-out fashion, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial heterogeneity of hotspot mutations and clonal relatedness in ovarian endometrioid carcinoma. 卵巢子宫内膜样癌热点突变及克隆亲缘关系的空间异质性。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-08 DOI: 10.1002/1878-0261.70347

Takahito Ashihara, Kosuke Murakami, Shiro Takamatsu, Akiko Kanto, Seiichi Mori, Tomoyuki Otani, Kazuko Sakai, Yasushi Kotani, Kazuto Nishio, Kaoru Abiko, Noriomi Matsumura

{"title":"Spatial heterogeneity of hotspot mutations and clonal relatedness in ovarian endometrioid carcinoma.","authors":"Takahito Ashihara, Kosuke Murakami, Shiro Takamatsu, Akiko Kanto, Seiichi Mori, Tomoyuki Otani, Kazuko Sakai, Yasushi Kotani, Kazuto Nishio, Kaoru Abiko, Noriomi Matsumura","doi":"10.1002/1878-0261.70347","DOIUrl":"10.1002/1878-0261.70347","url":null,"abstract":"Ovarian endometrioid carcinoma (OEC) is a major histotype of endometriosis-associated ovarian carcinoma, yet the spatial distribution of cancer-associated mutations and the clonal relatedness of synchronous endometrial and ovarian carcinomas (SEOC) remain incompletely understood. In this study, we performed spatially controlled molecular profiling of OEC using laser capture microdissection, droplet digital PCR, targeted amplicon sequencing, and exploratory whole-exome sequencing. We analyzed multiple tumor regions and selected stromal compartments from OEC and SEOC cases to assess the intratumor distribution of hotspot mutations in CTNNB1, PIK3CA, and KRAS and to evaluate molecular relatedness between ovarian and endometrial lesions in SEOC. Cancer-associated mutation signals showed spatially heterogeneous distributions in a subset of histologically uniform OEC. In SEOC, shared alterations supported clonal relatedness in selected cases. Low-level hotspot mutation signals were also detected in microdissected stromal compartments immediately adjacent to tumor glands, although their cellular origin remains to be determined. These findings suggest that single-region molecular testing may underestimate spatial molecular heterogeneity in OEC and provide a framework for understanding the clonal relatedness of endometriosis-associated gynecologic carcinomas.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unique circulating miRNAome signatures captured with distinct molecular states in Lynch syndrome and sporadic colorectal cancer. 在Lynch综合征和散发性结直肠癌中捕获的具有不同分子状态的独特循环miRNAome特征。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-07 DOI: 10.1002/1878-0261.70338

Ramadhani Salum Chambuso, Md Shohel Ul Islam, Rosa M Xicola, Raj Ramesar, Xavier Llor, Sinclair Steele

{"title":"Unique circulating miRNAome signatures captured with distinct molecular states in Lynch syndrome and sporadic colorectal cancer.","authors":"Ramadhani Salum Chambuso, Md Shohel Ul Islam, Rosa M Xicola, Raj Ramesar, Xavier Llor, Sinclair Steele","doi":"10.1002/1878-0261.70338","DOIUrl":"10.1002/1878-0261.70338","url":null,"abstract":"Hereditary nonpolyposis colorectal cancer (HNPCC), usually termed Lynch syndrome (LS), is the most prevalent hereditary colorectal cancer syndrome, yet molecular biomarkers to differentiate nonmalignant from malignant LS cases remain limited. We performed a secondary analysis of the circulating miRNAome in 155 individuals, including healthy controls (CTRL), nonmalignant LS (H-LS), cancer-associated LS (C-LS), and sporadic colorectal cancer (CRC). We observed that LS variant heterozygotes, especially those without overt cancer, exhibit a transitional miRNAomic architecture distinct from both healthy controls and CRC patients in different age groups. Age-stratified differential expression and miRNA-mRNA network analyses revealed distinct regulatory hubs across groups. Group-specific miRNAs targeted oncogenic, immune, and DNA repair pathways. The analysis suggested that nonmalignant LS variant heterozygotes occupy a circulating miRNAome state distinct from both healthy controls and overt CRC, whereas C-LS and sporadic CRC shared selected malignant-associated miRNA features. To assess external concordance, we performed orthogonal validation of a prespecified six-miRNA panel in the independent GSE30454 primary colorectal tissue cohort, comprising normal, LS, sporadic MSI, and MSS samples. The composite panel preserved disease-axis structure across the external cohort, with strongest discrimination in biologically relevant mismatch repair-related contrasts. These findings suggest candidate circulating miRNA molecular states across LS and sporadic colorectal cancer.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular vesicle lipidomics liquid biopsy reveals systemic and tumor microenvironment metabolic reprogramming in ovarian cancer. 细胞外囊泡脂质组学液体活检揭示卵巢癌系统和肿瘤微环境代谢重编程。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-07 DOI: 10.1002/1878-0261.70327

Shikha Rani, Dominic Guanzon, Andrew Lai, Katherin Scholz-Romero, Sarah Reed, Edita Ritmejeryte, Rohan Lourie, Naven Chetty, Kaltin Ferguson, Carlos Salomon

{"title":"Extracellular vesicle lipidomics liquid biopsy reveals systemic and tumor microenvironment metabolic reprogramming in ovarian cancer.","authors":"Shikha Rani, Dominic Guanzon, Andrew Lai, Katherin Scholz-Romero, Sarah Reed, Edita Ritmejeryte, Rohan Lourie, Naven Chetty, Kaltin Ferguson, Carlos Salomon","doi":"10.1002/1878-0261.70327","DOIUrl":"10.1002/1878-0261.70327","url":null,"abstract":"Ovarian cancer is the most lethal gynecological malignancy, due to late-stage diagnosis, tumor heterogeneity, and lack of biomarkers for early detection. Extracellular vesicles (EVs) in plasma and ascites offer a minimally invasive source of tumor-derived information, yet their lipid composition and relationship to tumor heterogeneity remain poorly defined. We performed lipidomic profiling of EVs from plasma and ascites of high-grade serous ovarian cancer patients and from ovarian cancer and control cell lines to identify signatures of tumor progression and microenvironmental interactions. A lipid panel enriched in ovarian cancer EVs was evaluated in EVs and plasma across two independent cohorts (n = 146). Combined with CA125, this panel improved detection, particularly against benign adnexal masses, achieving an AUROC of 0.99 in the verification cohort in both formats. Ovarian cancer EVs preferentially accumulated triglycerides, including ether-linked species, whereas parental cells were enriched in phospholipids and ceramides. EV lipid signatures reflected tumor-associated metabolic reprogramming and captured tumor heterogeneity across cell models. These findings show that EV lipidomics from accessible biofluids offers a non-invasive window into ovarian cancer metabolism and candidate biomarkers for patient stratification and monitoring.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting the EpCAM-AXL axis to overcome drug resistance in lung cancer. 靶向EpCAM-AXL轴克服肺癌耐药。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-06 DOI: 10.1002/1878-0261.70342

Alexa Guerrero-Alba, Mark Shacker, Timothy P Fleming, Michael A Smith, Ross M Bremner, Narendra V Sankpal

{"title":"Targeting the EpCAM-AXL axis to overcome drug resistance in lung cancer.","authors":"Alexa Guerrero-Alba, Mark Shacker, Timothy P Fleming, Michael A Smith, Ross M Bremner, Narendra V Sankpal","doi":"10.1002/1878-0261.70342","DOIUrl":"10.1002/1878-0261.70342","url":null,"abstract":"Drug resistance significantly limits the long-term effectiveness of targeted therapies in lung cancer. AXL, a receptor tyrosine kinase (RTK), is a well-established driver of drug resistance in many cancers, including lung cancer. Epithelial cell adhesion molecule (EpCAM), which is commonly overexpressed in epithelial cancers, is also a critical signaling molecule. In this study, we elucidated the role of EpCAM in drug resistance and its mechanistic association with AXL. We found that soluble epithelial cell adhesion molecule (sEpCAM) expression robustly enhanced hallmark cancer phenotypes and promoted pro-survival functions by upregulating AXL expression. Gene expression and pathway analyses further identified significant alterations in core cancer signaling pathways, including NF-kB, STAT3, AKT, and ERK. The ectopic expression of sEpCAM concurrently upregulated endogenous EpCAM expression in the tumor environment. Functionally, sEpCAM confers broad resistance to conventional chemotherapy. Drug sensitivity assays revealed that proteasome inhibition effectively reversed the sEpCAM-induced drug resistance by reducing AXL protein levels. Translational analysis of the lung cancer patient cohort data indicated that patients with aggressive disease co-expressing EpCAM and AXL may be particularly amenable to proteasome-based therapy. Characterization of the EpCAM-AXL axis gene signature further uncovered connections to p53, integrin, and Rho GTPase signaling as well as an intriguing link to tumor immune evasion. Our findings suggest that EpCAM-AXL co-expression in a subset of patients with lung cancer serves as both a predictive biomarker and a promising therapeutic target to counteract treatment failure.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering IL-4 resistant proinflammatory human myeloid cells for cancer immunotherapy. 工程IL-4抵抗的促炎人骨髓细胞用于癌症免疫治疗。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-03 DOI: 10.1002/1878-0261.70346

Theresa Barberi, Alan D Friedman

{"title":"Engineering IL-4 resistant proinflammatory human myeloid cells for cancer immunotherapy.","authors":"Theresa Barberi, Alan D Friedman","doi":"10.1002/1878-0261.70346","DOIUrl":"https://doi.org/10.1002/1878-0261.70346","url":null,"abstract":"Adoptive transfer of proinflammatory myeloid cells enhances antitumor T-cell responses and limits tumor growth in murine models. Previous work identified transcription factors NF-κB p50 and STAT6 as key regulators whose inactivation enhances the inflammatory potential of murine myeloid cells. Herein, we translate murine findings to human cells and establish methods to generate proinflammatory myeloid cells from human marrow-derived CD34+ hematopoietic stem and progenitor cells (HSPCs). Using CRISPR-Cas9, we disrupted NFKB1, STAT6, both NFKB1 and STAT6, or NFKB1 and NFKB2 (encoding NF-κB p52), achieving robust loss of target proteins. We determined conditions for expanding HSPCs and differentiating them into monocytes. To evaluate proinflammatory potential under immune-suppressive conditions, edited monocytes were differentiated into macrophages, exposed to IL-4, and analyzed for gene expression. RNA sequencing revealed enhanced proinflammatory pathway activation in STAT6- and p50/STAT6-deficient macrophages, but not in p50- or p50/p52-deficient macrophages. Transcriptomic analysis was validated by measuring protein secretion of a subset of inflammatory mediators. These findings establish a strategy to generate proinflammatory human myeloid cells with potential clinical application in cancer immunotherapy. Future clinical evaluation will be required to determine whether STAT6-IMC or p50/STAT6-IMC exhibit superior therapeutic efficacy.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetics in cancer: from mechanisms to precision medicine. 癌症的表观遗传学：从机制到精准医学。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-01 DOI: 10.1002/1878-0261.70340

Sung Hee Baek

{"title":"Epigenetics in cancer: from mechanisms to precision medicine.","authors":"Sung Hee Baek","doi":"10.1002/1878-0261.70340","DOIUrl":"10.1002/1878-0261.70340","url":null,"abstract":"Epigenetics encompasses heritable yet reversible changes in gene expression that occur without alterations to the underlying DNA sequence. Through coordinated regulation of DNA methylation, histone modifications, chromatin remodeling, and higher-order chromatin organization, epigenetic mechanisms shape chromatin accessibility and transcriptional programs that govern cellular identity, plasticity, and tissue homeostasis. In cancer, disruption of the epigenetic landscape has emerged as a hallmark of tumor initiation, progression, metastasis, immune evasion, and therapeutic resistance. Unlike genetic alterations, epigenetic abnormalities are potentially reversible, making them attractive therapeutic targets. Recent advances in next-generation sequencing, single-cell and spatial multi-omics, chromatin profiling technologies, and computational biology have transformed our understanding of cancer epigenomes while accelerating the development of epigenetic therapies targeting diverse chromatin regulatory pathways. This Thematic Issue on Epigenetics in Cancer brings together leading experts to review recent conceptual and technological advances that are reshaping the field. Covering topics ranging from spatial and single-cell epigenomics to chromatin regulation, tumor plasticity, and emerging therapeutic strategies, the collection highlights how fundamental discoveries are driving translational innovation and precision oncology. We hope these articles will provide a valuable resource for researchers and clinicians while inspiring future advances in cancer epigenetics and epigenetic therapeutics.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":"20 10","pages":"2389-2392"},"PeriodicalIF":4.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Arginine methylation as a regulatory ratchet in cancer: From substrate selection to malignant-state stabilization. 精氨酸甲基化在癌症中的调节棘轮：从底物选择到恶性状态稳定。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-01 Epub Date: 2026-08-25 DOI: 10.1002/1878-0261.70322

So Hyun Kwon, Ji Min Lee

{"title":"Arginine methylation as a regulatory ratchet in cancer: From substrate selection to malignant-state stabilization.","authors":"So Hyun Kwon, Ji Min Lee","doi":"10.1002/1878-0261.70322","DOIUrl":"10.1002/1878-0261.70322","url":null,"abstract":"Arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is a widespread post-translational modification yet its regulatory logic in cancer remains incompletely framed. Unlike rapidly reversible modifications, arginine methylation operates through a persistence-prone, forward-biased logic shaped by the lack of a broadly acting demethylase system, multisite substrates, and ongoing methylation flux. Here, we propose a regulatory ratchet framework in which PRMT-dependent methylation can reinforce cellular states through cumulative and network-level effects rather than acting as a binary switch. We integrate PRMT subtype specificity and noncatalytic functions with a four-layer model of substrate selection spanning sequence, structural, localization, and environmental context. Persistence may arise at both mark and flux levels, while scaffold-like PRMT functions may sustain regulatory complexes independently of catalysis. In cancer, PRMT-compatible substrates are distributed across RNA processing, chromatin and transcriptional regulation, signaling, and metabolism, with methylation output shaped by dynamic inter-PRMT relationships. Together, these network-level interactions may reinforce cancer cell states while creating therapeutic vulnerabilities within a constrained methylation system, shifting attention from individual PRMT abundance toward the network architecture that sustains malignant programs.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2466-2489"},"PeriodicalIF":4.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting transcription factors associated with hemoglobinopathies: Lessons from successful interventions and implications for cancer. 靶向与血红蛋白病相关的转录因子：来自成功干预的经验教训及其对癌症的影响。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2026-10-01 Epub Date: 2026-07-16 DOI: 10.1002/1878-0261.70304

Meigen Yu, Puspa Das, Xing Zhang, Xiaodong Cheng

{"title":"Targeting transcription factors associated with hemoglobinopathies: Lessons from successful interventions and implications for cancer.","authors":"Meigen Yu, Puspa Das, Xing Zhang, Xiaodong Cheng","doi":"10.1002/1878-0261.70304","DOIUrl":"10.1002/1878-0261.70304","url":null,"abstract":"Sickle cell disease and cancer represent fundamentally distinct classes of human disease-one is driven by a defined mutation in β-globin, whereas the other arises through complex genetic and epigenetic alterations that reshape cellular identity and behavior. Despite these differences, both contexts illustrate how transcription factors, chromatin regulators, and cis-regulatory elements can impose disease-relevant gene expression states. In β-hemoglobinopathies, therapeutic reactivation of fetal hemoglobin through modulation of γ-globin (HBG1/2) regulatory pathways, most notably disruption of the erythroid-specific BCL11A enhancer, has emerged as a clinically validated strategy. These advances have been facilitated in part by the HUDEP-2 erythroid progenitor cell line, which provides a tractable adult erythroid model for identifying fetal hemoglobin regulators, validating their function, and evaluating relevant gene editing and gene-regulatory therapies. Many of the regulators implicated in γ-globin silencing, including BCL11A, ZBTB7A, NuRD-associated proteins, DNMT1, KDM1A/LSD1, MYB, and ATF4, also function in cancer-associated transcriptional or epigenetic networks. In cancer, these factors can support oncogenic transcription, tumor suppressor repression, impaired differentiation, stress adaptation, invasion, or therapy resistance. This review summarizes discoveries enabled by HUDEP-2 cells in fetal hemoglobin regulation and hemoglobinopathy therapeutic development, then discusses how these mechanisms provide conceptual parallels for understanding and targeting regulatory dependencies in cancer.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2533-2566"},"PeriodicalIF":4.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0