Colorectal mucinous adenocarcinoma (MAC), a distinct subtype of adenocarcinoma (AC) characterized by extracellular mucus production. However, the specific regulatory role of mucus production in MAC development remains underexplored. In this study, scRNA-seq analyses revealed that L1TD1 expression was significantly greater in MAC than in adjacent noncancerous tissues. L1TD1 is an RNA-binding protein that has been reported to regulate mRNA stability and stemness-associated transcriptional programs in cancer cells. Further experiments confirmed that L1TD1 expression was elevated in MAC compared to normal tissues and L1TD1 promoted mucus production and accelerated tumor cell proliferation and metastasis. Mechanistically, further analysis revealed the RNA recognition motif (RRM) domain of L1TD1 binds to the 3′ untranslated region (3’-UTR) of ABCC3 mRNA, thus increasing its stability. In addition, ABCC3 inhibition reversed L1TD1 overexpression-induced mucus production and MAC progression. Collectively our findings demonstrate that L1TD1 binds to the GUGU motif within ABCC3 mRNA and upregulates ABCC3 expression, which subsequently activates the MAPK signaling pathway and promotes mucin production and accelerates MAC progression. These results also provide essential evidence for investigating the mechanisms of mucus production and tumor progression in MAC.
{"title":"L1TD1 promotes colorectal mucinous adenocarcinoma progression by enhancing ABCC3 mRNA stability","authors":"Haoqing He, Jinqiang Yuan, Haoran Wang, Lili Chen, Bingxu Liu, Zhonghui Cui, Yunfei Xu, Guangyong Zhang, Hui Yang","doi":"10.1038/s41388-026-03716-w","DOIUrl":"10.1038/s41388-026-03716-w","url":null,"abstract":"Colorectal mucinous adenocarcinoma (MAC), a distinct subtype of adenocarcinoma (AC) characterized by extracellular mucus production. However, the specific regulatory role of mucus production in MAC development remains underexplored. In this study, scRNA-seq analyses revealed that L1TD1 expression was significantly greater in MAC than in adjacent noncancerous tissues. L1TD1 is an RNA-binding protein that has been reported to regulate mRNA stability and stemness-associated transcriptional programs in cancer cells. Further experiments confirmed that L1TD1 expression was elevated in MAC compared to normal tissues and L1TD1 promoted mucus production and accelerated tumor cell proliferation and metastasis. Mechanistically, further analysis revealed the RNA recognition motif (RRM) domain of L1TD1 binds to the 3′ untranslated region (3’-UTR) of ABCC3 mRNA, thus increasing its stability. In addition, ABCC3 inhibition reversed L1TD1 overexpression-induced mucus production and MAC progression. Collectively our findings demonstrate that L1TD1 binds to the GUGU motif within ABCC3 mRNA and upregulates ABCC3 expression, which subsequently activates the MAPK signaling pathway and promotes mucin production and accelerates MAC progression. These results also provide essential evidence for investigating the mechanisms of mucus production and tumor progression in MAC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 12","pages":"1071-1086"},"PeriodicalIF":7.3,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03716-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147348707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents a promising therapeutic target. In this study, we identified the natural compound ginkgetin (Gink) as a novel GRP78 inhibitor. Cellular thermal shift assays, surface plasmon resonance, and mutagenesis studies revealed that Gink directly binds to GRP78, with K296 serving as a key interaction site. In vitro, Gink suppressed osteosarcoma cell proliferation, migration, and invasion while inducing apoptosis and autophagy by activating the PERK-eIF2α-ATF4 pathway. Co-immunoprecipitation assays showed that Gink competitively disrupted GRP78-PERK interaction. In orthotopic and patient-derived xenograft models, Gink treatment markedly attenuated tumor growth and metastasis. Gink also reprogrammed the tumor immune microenvironment by reducing M2 macrophage polarization and synergizing with anti-PD1 therapy to enhance CD8+ T-cell activity. Accordingly, Gink could be developed as a GRP78-targeting agent that triggers ER stress and immune activation, offering a dual-pronged therapeutic strategy against osteosarcoma.
{"title":"Ginkgetin targets GRP78 to induce dual pathways of ER stress and immune activation in osteosarcoma","authors":"Wenyuan Xu, Tongtong Liu, Xinglong Ma, He Dong, Yinghao Cao, Guanyi Li, Zhuoying Wang, Yingqi Hua, Zhengdong Cai, Mengxiong Sun, Jingjie Li, Tao Zhang","doi":"10.1038/s41388-026-03704-0","DOIUrl":"10.1038/s41388-026-03704-0","url":null,"abstract":"Osteosarcoma is an aggressive malignancy characterized by rapid proliferation and a propensity for metastasis. The endoplasmic reticulum (ER) chaperone GRP78, a critical regulator of osteosarcoma progression, represents a promising therapeutic target. In this study, we identified the natural compound ginkgetin (Gink) as a novel GRP78 inhibitor. Cellular thermal shift assays, surface plasmon resonance, and mutagenesis studies revealed that Gink directly binds to GRP78, with K296 serving as a key interaction site. In vitro, Gink suppressed osteosarcoma cell proliferation, migration, and invasion while inducing apoptosis and autophagy by activating the PERK-eIF2α-ATF4 pathway. Co-immunoprecipitation assays showed that Gink competitively disrupted GRP78-PERK interaction. In orthotopic and patient-derived xenograft models, Gink treatment markedly attenuated tumor growth and metastasis. Gink also reprogrammed the tumor immune microenvironment by reducing M2 macrophage polarization and synergizing with anti-PD1 therapy to enhance CD8+ T-cell activity. Accordingly, Gink could be developed as a GRP78-targeting agent that triggers ER stress and immune activation, offering a dual-pronged therapeutic strategy against osteosarcoma.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"1042-1056"},"PeriodicalIF":7.3,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147348746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glioblastoma (GB) is a highly complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Splicing factors play a pivotal role in processing nascent pre-mRNA and are important in the progression of cancer, making them promising molecular targets. In this study, we demonstrate that the DEAD-box helicase 39 A (DDX39A), a RNA helicase with several important roles in RNA metabolism and cellular processes, is significantly upregulated in GB and is primarily expressed in tumor cells, leading to an immunosuppressive macrophage polarization. Through in vitro and in vivo studies, we demonstrate that reducing DDX39A expression in GB results in reduced tumor growth and invasion. Mechanistically, through RNA-seq and RIP-seq, we identified WISP1 as a critical downstream effector of DDX39A. DDX39A stabilizes WISP1 pre-mRNA through alternative splicing regulation, thereby activating the AKT signaling pathway. We further demonstrate that WISP1, when secreted by tumor cells, functions as a paracrine signaling molecule that promotes the development of immunosuppressive tumor-associated macrophages (TAMs). Additionally, we demonstrate that Fluphenazine hydrochloride binds to and inhibits DDX39A, thereby suppressing GB growth, invasion, and the immunosuppressive function of macrophages. DDX39A thus represents a potential candidate for glioma-targeted therapy.
{"title":"The multifunctional RNA helicase DDX39A drives glioblastoma progression by modulating WISP1 alternative splicing that induces an immunosuppressive macrophage polarization","authors":"Yan Zhang, Zhiwei Xue, Naibin Zhang, Yuehua Zhu, YanZhao Wu, Meilin Lv, Zhihan Zhang, Feiyu Mu, Wenchen Xing, Ziyi Tang, Chunjie Wang, Zhiyi Xue, Wenjing Zhou, Xiaofei Liu, Xingang Li, Rolf Bjerkvig, Bin Huang, Mingzhi Han, Jian Wang, Donghai Wang","doi":"10.1038/s41388-026-03715-x","DOIUrl":"10.1038/s41388-026-03715-x","url":null,"abstract":"Glioblastoma (GB) is a highly complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Splicing factors play a pivotal role in processing nascent pre-mRNA and are important in the progression of cancer, making them promising molecular targets. In this study, we demonstrate that the DEAD-box helicase 39 A (DDX39A), a RNA helicase with several important roles in RNA metabolism and cellular processes, is significantly upregulated in GB and is primarily expressed in tumor cells, leading to an immunosuppressive macrophage polarization. Through in vitro and in vivo studies, we demonstrate that reducing DDX39A expression in GB results in reduced tumor growth and invasion. Mechanistically, through RNA-seq and RIP-seq, we identified WISP1 as a critical downstream effector of DDX39A. DDX39A stabilizes WISP1 pre-mRNA through alternative splicing regulation, thereby activating the AKT signaling pathway. We further demonstrate that WISP1, when secreted by tumor cells, functions as a paracrine signaling molecule that promotes the development of immunosuppressive tumor-associated macrophages (TAMs). Additionally, we demonstrate that Fluphenazine hydrochloride binds to and inhibits DDX39A, thereby suppressing GB growth, invasion, and the immunosuppressive function of macrophages. DDX39A thus represents a potential candidate for glioma-targeted therapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"1026-1041"},"PeriodicalIF":7.3,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03715-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-28DOI: 10.1038/s41388-026-03718-8
Abbey E. Williams, Erica J. Hoffmann, David R. Inman, Metti K. Gari, Changyan Zhou, Brian M. Burkel, Nour Haidar, Yueran Pan, Megan Halambeck, Brittney N. Moore, Kari B. Wisinski, Stephanie M. McGregor, Sheena C. Kerr, Lisa M. Arendt, Suzanne M. Ponik
Recent epidemiological studies suggest that breast density and obesity together increase breast cancer risk. Although these risk factors have been explored individually, little is known about how they combine to alter the tumor immune microenvironment (TIME) and promote disease progression. To address this gap, we developed a murine model of both risk factors. Spatial analysis of the TIME revealed macrophages and T-cells predominantly localized in the stroma of both risk factor groups, indicating an immune exclusion phenotype. Mice with dual risk factors had significantly increased lung metastasis. To establish the human relevance of this model, we interrogated the TIME in biopsies from 158 patients with invasive ductal carcinoma and 10 years of follow-up data. We found that patients with both risk factors had the highest incidence of metastasis (45%). Furthermore, spatial immune profiling revealed exacerbated stromal localization of macrophages and T-cells in the dual risk factor group that progressed to metastasis. Overall, we uncovered an immune exclusion phenotype in metastatic breast cancer patients with obesity and breast density, and we present a relevant murine model that parallels human disease. The murine model will enable future investigation into therapies that intercept the mechanisms by which dual risk factors modulate the TIME.
{"title":"Obesity and breast density enhance immune exclusion in the primary tumor microenvironment and promote breast cancer metastasis","authors":"Abbey E. Williams, Erica J. Hoffmann, David R. Inman, Metti K. Gari, Changyan Zhou, Brian M. Burkel, Nour Haidar, Yueran Pan, Megan Halambeck, Brittney N. Moore, Kari B. Wisinski, Stephanie M. McGregor, Sheena C. Kerr, Lisa M. Arendt, Suzanne M. Ponik","doi":"10.1038/s41388-026-03718-8","DOIUrl":"10.1038/s41388-026-03718-8","url":null,"abstract":"Recent epidemiological studies suggest that breast density and obesity together increase breast cancer risk. Although these risk factors have been explored individually, little is known about how they combine to alter the tumor immune microenvironment (TIME) and promote disease progression. To address this gap, we developed a murine model of both risk factors. Spatial analysis of the TIME revealed macrophages and T-cells predominantly localized in the stroma of both risk factor groups, indicating an immune exclusion phenotype. Mice with dual risk factors had significantly increased lung metastasis. To establish the human relevance of this model, we interrogated the TIME in biopsies from 158 patients with invasive ductal carcinoma and 10 years of follow-up data. We found that patients with both risk factors had the highest incidence of metastasis (45%). Furthermore, spatial immune profiling revealed exacerbated stromal localization of macrophages and T-cells in the dual risk factor group that progressed to metastasis. Overall, we uncovered an immune exclusion phenotype in metastatic breast cancer patients with obesity and breast density, and we present a relevant murine model that parallels human disease. The murine model will enable future investigation into therapies that intercept the mechanisms by which dual risk factors modulate the TIME.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"1057-1064"},"PeriodicalIF":7.3,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03718-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26DOI: 10.1038/s41388-026-03698-9
Begoña Caballero-Ruiz, Rosa Bordone, Sonia Coni, Danai S. Gkotsi, Eva Gonzalez, Gianluca Canettieri, Natalia A. Riobo-Del Galdo
Loss of function mutations of the Hedgehog receptor PTCH1 are oncogenic drivers in some skin and brain cancers. We recently reported mutations in exons encoding the C-terminal tail of PTCH1 in colon cancer, which result in premature truncation but do not impair canonical Hedgehog signalling. In this study, we show that colon cancer cells engineered by CRISPR/Cas9 to express endogenous truncated PTCH1 have enhanced proliferation, colony formation, anchorage-independent growth and form larger tumours in vivo than isogenic cells expressing wild-type PTCH1. Analysis of the mechanisms underlying this growth advantage revealed profound transcriptional changes and unexpectedly, upregulation of GLI1 and GLI2 by a Smoothened-independent route, which proved to be necessary for the proliferative advantage. Furthermore, we found that truncation of PTCH1 C-tail upregulated several cancer-related pathways, including EGFR and Ras signalling and led to enhanced GLI-dependent PI3K activation, which exerted a positive feedback regulation on GLI expression and activity. Accordingly, PTCH1 mutant cells were highly sensitive to PI3K and GLI inhibitors and were only partially sensitive to EGFR and MEK inhibitors. Altogether, these findings reveal that PTCH1 C-tail truncating mutations promote colon cancer tumourigenesis through a non-canonical GLI-PI3K positive loop.
{"title":"Partial truncation of the C-terminal domain of PTCH1 in cancer promotes tumourigenesis by non-canonical activation of a GLI-PI3K loop","authors":"Begoña Caballero-Ruiz, Rosa Bordone, Sonia Coni, Danai S. Gkotsi, Eva Gonzalez, Gianluca Canettieri, Natalia A. Riobo-Del Galdo","doi":"10.1038/s41388-026-03698-9","DOIUrl":"10.1038/s41388-026-03698-9","url":null,"abstract":"Loss of function mutations of the Hedgehog receptor PTCH1 are oncogenic drivers in some skin and brain cancers. We recently reported mutations in exons encoding the C-terminal tail of PTCH1 in colon cancer, which result in premature truncation but do not impair canonical Hedgehog signalling. In this study, we show that colon cancer cells engineered by CRISPR/Cas9 to express endogenous truncated PTCH1 have enhanced proliferation, colony formation, anchorage-independent growth and form larger tumours in vivo than isogenic cells expressing wild-type PTCH1. Analysis of the mechanisms underlying this growth advantage revealed profound transcriptional changes and unexpectedly, upregulation of GLI1 and GLI2 by a Smoothened-independent route, which proved to be necessary for the proliferative advantage. Furthermore, we found that truncation of PTCH1 C-tail upregulated several cancer-related pathways, including EGFR and Ras signalling and led to enhanced GLI-dependent PI3K activation, which exerted a positive feedback regulation on GLI expression and activity. Accordingly, PTCH1 mutant cells were highly sensitive to PI3K and GLI inhibitors and were only partially sensitive to EGFR and MEK inhibitors. Altogether, these findings reveal that PTCH1 C-tail truncating mutations promote colon cancer tumourigenesis through a non-canonical GLI-PI3K positive loop.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"1013-1025"},"PeriodicalIF":7.3,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03698-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-25DOI: 10.1038/s41388-026-03700-4
Dayu Huang, Dongdong Wang, Youbo Wang, Xuan Wang, Chang He, Yu Du, Qinyun Ma, Xiaofeng Chen, An Wang
Esophageal squamous cell cancer (ESCC) remains an aggressive malignant tumor with limited therapeutic options and poor prognosis. This study aims to uncover novel diagnostic markers and therapeutic targets by investigating molecular drivers of ESCC pathogenesis using integrated omics and functional assays. The gene expression profiles of ESCC tissues were compared with those of normal tissues. SEC14L4 expression was evaluated through qPCR, Western blot, and immunohistochemistry (IHC). Functional roles of SEC14L4 were assessed through cell proliferation, colony formation, apoptosis, migration, and invasion assays. Co-immunoprecipitation (Co-IP) and mass spectrometry were used to discover SEC14L4-interacting proteins. Ubiquitination assays assessed the degradation of DDX3X. The MAPK pathway and ferroptosis markers were analyzed by Western blot to investigate the downstream effects of SEC14L4. In vivo tumor models were used to validate SEC14L4’s oncogenic role. SEC14L4 was markedly overexpressed in ESCC tissues, correlating with advanced tumor stage and reduced overall survival. In vitro, SEC14L4 promoted ESCC cell proliferation, migration, and colony formation, while inhibiting apoptosis, while its knockdown reduced these effects. DDX3X overexpression rescued these phenotypes. Co-IP and mass spectrometry confirmed a direct interaction between SEC14L4 and DDX3X, and SEC14L4 was found to inhibit DDX3X ubiquitination via RNF39. SEC14L4 promotes ESCC progression by activating the MAPK signaling pathway and inhibiting ferroptosis. In vivo, SEC14L4 knockdown significantly inhibited tumor growth. SEC14L4 facilitates ESCC development by inhibiting the ubiquitination and degradation of DDX3X by RNF39.
{"title":"SEC14L4 promotes the development of esophageal squamous cell cancer by inhibiting the ubiquitination and degradation of DDX3X via RNF39","authors":"Dayu Huang, Dongdong Wang, Youbo Wang, Xuan Wang, Chang He, Yu Du, Qinyun Ma, Xiaofeng Chen, An Wang","doi":"10.1038/s41388-026-03700-4","DOIUrl":"10.1038/s41388-026-03700-4","url":null,"abstract":"Esophageal squamous cell cancer (ESCC) remains an aggressive malignant tumor with limited therapeutic options and poor prognosis. This study aims to uncover novel diagnostic markers and therapeutic targets by investigating molecular drivers of ESCC pathogenesis using integrated omics and functional assays. The gene expression profiles of ESCC tissues were compared with those of normal tissues. SEC14L4 expression was evaluated through qPCR, Western blot, and immunohistochemistry (IHC). Functional roles of SEC14L4 were assessed through cell proliferation, colony formation, apoptosis, migration, and invasion assays. Co-immunoprecipitation (Co-IP) and mass spectrometry were used to discover SEC14L4-interacting proteins. Ubiquitination assays assessed the degradation of DDX3X. The MAPK pathway and ferroptosis markers were analyzed by Western blot to investigate the downstream effects of SEC14L4. In vivo tumor models were used to validate SEC14L4’s oncogenic role. SEC14L4 was markedly overexpressed in ESCC tissues, correlating with advanced tumor stage and reduced overall survival. In vitro, SEC14L4 promoted ESCC cell proliferation, migration, and colony formation, while inhibiting apoptosis, while its knockdown reduced these effects. DDX3X overexpression rescued these phenotypes. Co-IP and mass spectrometry confirmed a direct interaction between SEC14L4 and DDX3X, and SEC14L4 was found to inhibit DDX3X ubiquitination via RNF39. SEC14L4 promotes ESCC progression by activating the MAPK signaling pathway and inhibiting ferroptosis. In vivo, SEC14L4 knockdown significantly inhibited tumor growth. SEC14L4 facilitates ESCC development by inhibiting the ubiquitination and degradation of DDX3X by RNF39.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"999-1012"},"PeriodicalIF":7.3,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-20DOI: 10.1038/s41388-026-03699-8
Łukasz Szymański, Tino Schenk, Michał Ławiński, Annamaria Brioli, Arthur Zelent
Retinoic acid signaling, mediated through its receptors (RARs and RXRs), plays a fundamental role in regulating cell differentiation, proliferation, and apoptosis. While well established in hematologic malignancies, particularly acute promyelocytic leukemia, its therapeutic potential in breast cancer remains underexplored. Emerging evidence has identified aberrant epigenetic regulation of retinoic acid receptors as a central mechanism of resistance to retinoic acid. This review integrates recent advances in epigenetic control, receptor biology, and translational studies to re-evaluate the therapeutic potential of retinoic acid in breast cancer. Among the many factors that influence retinoic acid signaling are reduced receptor expression and altered intracellular delivery of retinoic acid. Promoter hypermethylation and histone deacetylation silence RARβ2 and disrupt canonical retinoic acid transcriptional networks, while imbalanced intracellular routing via CRABP2 and FABP5 and subtype-specific expression of RAR isoforms further determine therapeutic outcomes. Luminal tumors with preserved RARα and CRABP2 expression display strong retinoic acid sensitivity, in contrast to HER2-enriched and triple-negative subtypes, where MYC-driven CRABP2 suppression and DNA hypermethylation confer retinoid resistance. Epigenetic therapies using DNMT or HDAC inhibitors can restore RARβ2 expression and resensitize tumors. Combination regimens such as retinoic acid with entinostat and doxorubicin achieve potent antitumor synergy in preclinical models. Retinoic acid also remodels the tumor microenvironment by modulating angiogenesis, fibroblast activation, and immune responses, although stromal RARβ signaling can paradoxically promote tumor progression. Early clinical trials lacked biomarker stratification and were limited by unfavorable pharmacokinetics, likely obscuring therapeutic benefit. Future clinical development should focus on biomarker-driven patient stratification, pharmacological optimization, and rational combination strategies that integrate retinoids with targeted or immune-based therapies. Notably, emerging methylation-based classifiers that identify retinoid-responsive triple-negative breast cancer subsets, together with the paradoxical pro-tumorigenic effects of stromal RARβ, underscore the novelty and translational significance of integrating tumor-intrinsic and microenvironmental determinants of retinoid sensitivity. Together, these approaches may help re-establish functional retinoid signaling and realize the therapeutic potential of retinoic acid in breast cancer.
{"title":"Association of retinoids, retinoic acid receptors and epigenetics in breast cancer","authors":"Łukasz Szymański, Tino Schenk, Michał Ławiński, Annamaria Brioli, Arthur Zelent","doi":"10.1038/s41388-026-03699-8","DOIUrl":"10.1038/s41388-026-03699-8","url":null,"abstract":"Retinoic acid signaling, mediated through its receptors (RARs and RXRs), plays a fundamental role in regulating cell differentiation, proliferation, and apoptosis. While well established in hematologic malignancies, particularly acute promyelocytic leukemia, its therapeutic potential in breast cancer remains underexplored. Emerging evidence has identified aberrant epigenetic regulation of retinoic acid receptors as a central mechanism of resistance to retinoic acid. This review integrates recent advances in epigenetic control, receptor biology, and translational studies to re-evaluate the therapeutic potential of retinoic acid in breast cancer. Among the many factors that influence retinoic acid signaling are reduced receptor expression and altered intracellular delivery of retinoic acid. Promoter hypermethylation and histone deacetylation silence RARβ2 and disrupt canonical retinoic acid transcriptional networks, while imbalanced intracellular routing via CRABP2 and FABP5 and subtype-specific expression of RAR isoforms further determine therapeutic outcomes. Luminal tumors with preserved RARα and CRABP2 expression display strong retinoic acid sensitivity, in contrast to HER2-enriched and triple-negative subtypes, where MYC-driven CRABP2 suppression and DNA hypermethylation confer retinoid resistance. Epigenetic therapies using DNMT or HDAC inhibitors can restore RARβ2 expression and resensitize tumors. Combination regimens such as retinoic acid with entinostat and doxorubicin achieve potent antitumor synergy in preclinical models. Retinoic acid also remodels the tumor microenvironment by modulating angiogenesis, fibroblast activation, and immune responses, although stromal RARβ signaling can paradoxically promote tumor progression. Early clinical trials lacked biomarker stratification and were limited by unfavorable pharmacokinetics, likely obscuring therapeutic benefit. Future clinical development should focus on biomarker-driven patient stratification, pharmacological optimization, and rational combination strategies that integrate retinoids with targeted or immune-based therapies. Notably, emerging methylation-based classifiers that identify retinoid-responsive triple-negative breast cancer subsets, together with the paradoxical pro-tumorigenic effects of stromal RARβ, underscore the novelty and translational significance of integrating tumor-intrinsic and microenvironmental determinants of retinoid sensitivity. Together, these approaches may help re-establish functional retinoid signaling and realize the therapeutic potential of retinoic acid in breast cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"961-970"},"PeriodicalIF":7.3,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03699-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-19DOI: 10.1038/s41388-026-03695-y
Mariana Acevedo, Florence Dô, Firas El-Mortada, Pierre-Luc Tanguay, Laure Voisin, Thibault Houles, Geneviève Lavoie, David Allard, Philippe P. Roux, John Stagg, Samuel Doré, Logan Walsh, Jimmy Fourtounis, Eric Bonneil, Sylvain Meloche, Marc J. Servant
Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer (CRC). Here, we identify the deubiquitinating enzyme USP17 as a critical regulator of β-catenin stability and activity in CRC. We demonstrate that USP17 directly interacts with and deubiquitinates β-catenin, preventing its degradation and enhancing its stability. CRISPR/Cas9-mediated knockdown of USP17 in CRC-derived cell lines significantly reduced β-catenin levels and suppressed epithelial-mesenchymal transition (EMT), as evidenced by distinct morphological changes and altered expression of classical EMT markers. USP17 depletion reduced the proliferation of CRC cell lines and impaired CRC tumor growth in vivo. Conversely, USP17 overexpression in immortalized rat enterocytes elevated β-catenin levels and enhanced KRAS-induced cell proliferation. RNA sequencing and quantitative proteomic analysis of USP17-depleted CRC cells revealed significant suppression of the transcriptional coactivator function of β-catenin, impacting key oncogenic-related pathways. Our findings establish USP17 as a key regulator of β-catenin signaling and highlight its potential as a candidate therapeutic target in CRC.
{"title":"The deubiquitinase USP17 regulates the expression and activity of the oncogenic driver β-catenin in colorectal cancer","authors":"Mariana Acevedo, Florence Dô, Firas El-Mortada, Pierre-Luc Tanguay, Laure Voisin, Thibault Houles, Geneviève Lavoie, David Allard, Philippe P. Roux, John Stagg, Samuel Doré, Logan Walsh, Jimmy Fourtounis, Eric Bonneil, Sylvain Meloche, Marc J. Servant","doi":"10.1038/s41388-026-03695-y","DOIUrl":"10.1038/s41388-026-03695-y","url":null,"abstract":"Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer (CRC). Here, we identify the deubiquitinating enzyme USP17 as a critical regulator of β-catenin stability and activity in CRC. We demonstrate that USP17 directly interacts with and deubiquitinates β-catenin, preventing its degradation and enhancing its stability. CRISPR/Cas9-mediated knockdown of USP17 in CRC-derived cell lines significantly reduced β-catenin levels and suppressed epithelial-mesenchymal transition (EMT), as evidenced by distinct morphological changes and altered expression of classical EMT markers. USP17 depletion reduced the proliferation of CRC cell lines and impaired CRC tumor growth in vivo. Conversely, USP17 overexpression in immortalized rat enterocytes elevated β-catenin levels and enhanced KRAS-induced cell proliferation. RNA sequencing and quantitative proteomic analysis of USP17-depleted CRC cells revealed significant suppression of the transcriptional coactivator function of β-catenin, impacting key oncogenic-related pathways. Our findings establish USP17 as a key regulator of β-catenin signaling and highlight its potential as a candidate therapeutic target in CRC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"989-998"},"PeriodicalIF":7.3,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite advancements in diagnostics and treatment, lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Identifying novel molecular mechanisms that regulate the progression of LUAD is crucial for improving therapeutic outcomes. Our study reveals that CRTAC1, a natural tumor suppressor, can block the integrin pathway and inhibit the growth and metastasis of LUAD cells. Specifically, our study reveals that CRTAC1 is downregulated significantly in LUAD tissues and that its expression correlates positively with patient survival. Functionally, CRTAC1 inhibits the proliferation, migration, and invasion of LUAD cells both in vitro and in vivo by suppressing integrin/FAK signaling. These findings highlight CRTAC1 as a potential therapeutic target for LUAD, offering new avenues for treatment strategies aimed at reducing tumor progression.
{"title":"CRTAC1 inhibits progression of lung adenocarcinoma by suppressing integrin/FAK signaling","authors":"Yu Liu, Yuanyuan Chang, Haiying Li, Junyu Wang, Honglei Jin, Chuanshu Huang, Lingling Zhao, Qipeng Xie, Haishan Huang","doi":"10.1038/s41388-026-03691-2","DOIUrl":"10.1038/s41388-026-03691-2","url":null,"abstract":"Despite advancements in diagnostics and treatment, lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Identifying novel molecular mechanisms that regulate the progression of LUAD is crucial for improving therapeutic outcomes. Our study reveals that CRTAC1, a natural tumor suppressor, can block the integrin pathway and inhibit the growth and metastasis of LUAD cells. Specifically, our study reveals that CRTAC1 is downregulated significantly in LUAD tissues and that its expression correlates positively with patient survival. Functionally, CRTAC1 inhibits the proliferation, migration, and invasion of LUAD cells both in vitro and in vivo by suppressing integrin/FAK signaling. These findings highlight CRTAC1 as a potential therapeutic target for LUAD, offering new avenues for treatment strategies aimed at reducing tumor progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 10","pages":"946-960"},"PeriodicalIF":7.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite advancements in therapeutic strategies, metastatic prostate cancer (mPCa) remains challenging to treat, with limited clinical efficacy and poor prognosis. Anoikis resistance in tumor cells is crucial for their survival in the vascular system and plays a key role in metastasis. Therefore, investigating the molecular mechanisms of metastasis and anoikis resistance is essential for identifying novel therapeutic targets and strategies. In this study, we found that YEATS domain-containing 2 (YEATS2) plays a critical role in promoting PCa metastasis by suppressing anoikis. We observed that YEATS2 expression was elevated in mPCa and associated with poor clinical outcomes. Knockdown of YEATS2 reduced the metastatic potential of PCa cells both in vivo and in vitro, whereas its overexpression inhibited anoikis and promoted metastasis by upregulating the expression of the DNA damage repair gene RAD50. Mechanistically, YEATS2 increases chromatin accessibility at the RAD50 promoter region by recognizing H3K27ac and subsequently recruits the transcription factor NR2C2. Mirin suppressed lymph node metastasis of PCa cells in vivo. Our study demonstrated a novel function of the YEATS2/NR2C2/RAD50 axis in regulating DNA damage responses and anoikis resistance in PCa metastasis, highlighting an important pathway that drives metastatic progression and offering potential new strategies for treating mPCa.
{"title":"YEATS2 promotes DNA repair and induces anoikis resistance by enhancing chromatin accessibility to drive prostate cancer metastasis","authors":"Haoran Li, Yarong Song, Yukun Cong, Chuxiong Wang, Kang Chen, Chunyu Liu, Menghao Zhou, Yunjie Ju, Jinyu Chen, Liang Chen, Yifei Xing","doi":"10.1038/s41388-026-03696-x","DOIUrl":"10.1038/s41388-026-03696-x","url":null,"abstract":"Despite advancements in therapeutic strategies, metastatic prostate cancer (mPCa) remains challenging to treat, with limited clinical efficacy and poor prognosis. Anoikis resistance in tumor cells is crucial for their survival in the vascular system and plays a key role in metastasis. Therefore, investigating the molecular mechanisms of metastasis and anoikis resistance is essential for identifying novel therapeutic targets and strategies. In this study, we found that YEATS domain-containing 2 (YEATS2) plays a critical role in promoting PCa metastasis by suppressing anoikis. We observed that YEATS2 expression was elevated in mPCa and associated with poor clinical outcomes. Knockdown of YEATS2 reduced the metastatic potential of PCa cells both in vivo and in vitro, whereas its overexpression inhibited anoikis and promoted metastasis by upregulating the expression of the DNA damage repair gene RAD50. Mechanistically, YEATS2 increases chromatin accessibility at the RAD50 promoter region by recognizing H3K27ac and subsequently recruits the transcription factor NR2C2. Mirin suppressed lymph node metastasis of PCa cells in vivo. Our study demonstrated a novel function of the YEATS2/NR2C2/RAD50 axis in regulating DNA damage responses and anoikis resistance in PCa metastasis, highlighting an important pathway that drives metastatic progression and offering potential new strategies for treating mPCa.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 11","pages":"971-988"},"PeriodicalIF":7.3,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03696-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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