Pub Date : 2024-12-03DOI: 10.1038/s41388-024-03241-8
Hairui Wang, Hui Wang, Rui Wang, Yuanzhen Li, Zhipeng Wang, Wenshen Zhou, Li Deng, Xiyin Li, Li Zou, Qin Yang, Ren Lai, Xiaowei Qi, Jianyun Nie, Baowei Jiao
Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.
{"title":"Discovery of a molecular glue for EGFR degradation","authors":"Hairui Wang, Hui Wang, Rui Wang, Yuanzhen Li, Zhipeng Wang, Wenshen Zhou, Li Deng, Xiyin Li, Li Zou, Qin Yang, Ren Lai, Xiaowei Qi, Jianyun Nie, Baowei Jiao","doi":"10.1038/s41388-024-03241-8","DOIUrl":"10.1038/s41388-024-03241-8","url":null,"abstract":"Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 8","pages":"545-556"},"PeriodicalIF":6.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03241-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770882","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 : 2024-12-02DOI: 10.1038/s41388-024-03238-3
Likeng Ji, Jiongyu Chen, Lifang He, Fan Zhang, Zihao Deng, Jiediao Lin, Zhaochang Qi, Xi Luo, Armando E. Giuliano, Xiaojiang Cui, Stanley Li Lin, Yukun Cui
Approximately 70% of breast cancer (BC) cases are luminal-type (estrogen receptor-positive, ER+), suitable for endocrine therapy with tamoxifen as the most commonly used drug. However, about 30% of these patients develop tamoxifen resistance due to various mechanisms, primarily involving PI3K pathway activation through mutations or unknown pathways. Here, we discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110α protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110α inhibitor A66. Clinically, decreased N6AMT1 expression correlates with poor prognosis in luminal BC patients. In TamR BC organoids, combining tamoxifen with A66 further reduced growth compared to either treatment alone. Mechanistically, increased p110α levels result from inhibited degradation by E3 ubiquitin ligase NEDD4L. These findings suggest N6AMT1 as a potential luminal breast cancer biomarker and highlight the N6AMT1-p110α pathway as a therapeutic target to sensitize cells to tamoxifen.
{"title":"Reversal of endocrine resistance via N6AMT1-NEDD4L pathway-mediated p110α degradation","authors":"Likeng Ji, Jiongyu Chen, Lifang He, Fan Zhang, Zihao Deng, Jiediao Lin, Zhaochang Qi, Xi Luo, Armando E. Giuliano, Xiaojiang Cui, Stanley Li Lin, Yukun Cui","doi":"10.1038/s41388-024-03238-3","DOIUrl":"10.1038/s41388-024-03238-3","url":null,"abstract":"Approximately 70% of breast cancer (BC) cases are luminal-type (estrogen receptor-positive, ER+), suitable for endocrine therapy with tamoxifen as the most commonly used drug. However, about 30% of these patients develop tamoxifen resistance due to various mechanisms, primarily involving PI3K pathway activation through mutations or unknown pathways. Here, we discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110α protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110α inhibitor A66. Clinically, decreased N6AMT1 expression correlates with poor prognosis in luminal BC patients. In TamR BC organoids, combining tamoxifen with A66 further reduced growth compared to either treatment alone. Mechanistically, increased p110α levels result from inhibited degradation by E3 ubiquitin ligase NEDD4L. These findings suggest N6AMT1 as a potential luminal breast cancer biomarker and highlight the N6AMT1-p110α pathway as a therapeutic target to sensitize cells to tamoxifen.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 8","pages":"530-544"},"PeriodicalIF":6.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03238-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770795","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}
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and poses a treatment challenge due to high recurrence risk. Consequently, there is an urgent need for novel and efficacious therapies targeting TNBC. In this context, our study delineates the identification and characterization of a long non-coding RNA (lncRNA)-derived micropeptide miPEP205. Notably, the micropeptide exerts a significant inhibitory effect on the growth and metastasis of TNBC. Moreover, we observed a substantial down-regulation of micropeptide expression in clinical samples, which was markedly associated with a poor prognosis. Mechanistically, our research demonstrated that EGR3 governs lncRNA MIR205HG and the micropeptide expression, while miPEP205 boosts GSK-3β phosphorylation at Tyr216. This cascade causes β-catenin degradation, deactivating the GSK-3β/β-catenin signaling pathway and ultimately inhibits TNBC progression. Remarkably, our experiments in the spontaneous breast cancer mice model MMTV-PyMT demonstrated that the introduction of the miPEP205 gene or exogenous administration of the micropeptide miPEP205 significantly curtailed tumor growth and lung metastasis, and enhanced the overall survival among tumor-bearing mice. In conclusion, our study uncovers a previously uncharacterized micropeptide derived from a lncRNA, showcasing potent antitumor properties. These findings position miPEP205 as a promising novel target for therapeutic intervention in TNBC.
{"title":"A novel micropeptide miPEP205 suppresses the growth and metastasis of TNBC","authors":"Zheng Zhang, Fanrong Li, Xiaoxiao Dai, Jieqiong Deng, Yirong Wang, Shenghua Zhang, Wei Liu, Ying Xie, Yacheng Pan, Jieyu Wang, Tong Zhao, Shuang Wang, Wanqiu Li, Congnan Jin, Hebin Zhang, Jiachun Lu, Binbin Guo, Yifeng Zhou","doi":"10.1038/s41388-024-03240-9","DOIUrl":"10.1038/s41388-024-03240-9","url":null,"abstract":"Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and poses a treatment challenge due to high recurrence risk. Consequently, there is an urgent need for novel and efficacious therapies targeting TNBC. In this context, our study delineates the identification and characterization of a long non-coding RNA (lncRNA)-derived micropeptide miPEP205. Notably, the micropeptide exerts a significant inhibitory effect on the growth and metastasis of TNBC. Moreover, we observed a substantial down-regulation of micropeptide expression in clinical samples, which was markedly associated with a poor prognosis. Mechanistically, our research demonstrated that EGR3 governs lncRNA MIR205HG and the micropeptide expression, while miPEP205 boosts GSK-3β phosphorylation at Tyr216. This cascade causes β-catenin degradation, deactivating the GSK-3β/β-catenin signaling pathway and ultimately inhibits TNBC progression. Remarkably, our experiments in the spontaneous breast cancer mice model MMTV-PyMT demonstrated that the introduction of the miPEP205 gene or exogenous administration of the micropeptide miPEP205 significantly curtailed tumor growth and lung metastasis, and enhanced the overall survival among tumor-bearing mice. In conclusion, our study uncovers a previously uncharacterized micropeptide derived from a lncRNA, showcasing potent antitumor properties. These findings position miPEP205 as a promising novel target for therapeutic intervention in TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 8","pages":"513-529"},"PeriodicalIF":6.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770877","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 : 2024-11-29DOI: 10.1038/s41388-024-03221-y
Julia S. Scott, Loubna Al Ayadi, Emmanouela Epeslidou, Roan H. van Scheppingen, Anna Mukha, Lucas J. T. Kaaij, Catrin Lutz, Stefan Prekovic
Cohesin, a crucial regulator of genome organisation, plays a fundamental role in maintaining chromatin architecture as well as gene expression. Among its subunits, STAG2 stands out because of its frequent deleterious mutations in various cancer types, such as bladder cancer and melanoma. Loss of STAG2 function leads to significant alterations in chromatin structure, disrupts transcriptional regulation, and impairs DNA repair pathways. In this review, we explore the molecular mechanisms underlying cohesin-STAG2 function, highlighting its roles in healthy cells and its contributions to cancer biology, showing how STAG2 dysfunction promotes tumourigenesis and presents opportunities for targeted therapeutic interventions.
{"title":"Emerging roles of cohesin-STAG2 in cancer","authors":"Julia S. Scott, Loubna Al Ayadi, Emmanouela Epeslidou, Roan H. van Scheppingen, Anna Mukha, Lucas J. T. Kaaij, Catrin Lutz, Stefan Prekovic","doi":"10.1038/s41388-024-03221-y","DOIUrl":"10.1038/s41388-024-03221-y","url":null,"abstract":"Cohesin, a crucial regulator of genome organisation, plays a fundamental role in maintaining chromatin architecture as well as gene expression. Among its subunits, STAG2 stands out because of its frequent deleterious mutations in various cancer types, such as bladder cancer and melanoma. Loss of STAG2 function leads to significant alterations in chromatin structure, disrupts transcriptional regulation, and impairs DNA repair pathways. In this review, we explore the molecular mechanisms underlying cohesin-STAG2 function, highlighting its roles in healthy cells and its contributions to cancer biology, showing how STAG2 dysfunction promotes tumourigenesis and presents opportunities for targeted therapeutic interventions.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 5","pages":"277-287"},"PeriodicalIF":6.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755364","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 : 2024-11-29DOI: 10.1038/s41388-024-03239-2
Furong Huang, Kexin Li, Zhong Chen, Zhifen Cui, William Hankey, Kun Fang, Jingyue Yan, Hongyan Wang, Victor X. Jin, Yizhou Dong, Qianben Wang
Acquired resistance to androgen receptor (AR)-targeted therapies underscores the need to identify alternative therapeutic targets for treating lethal prostate cancer. In this study, we evaluated the prognostic significance of 1635 human transcription factors (TFs) by analyzing castration-resistant prostate cancer (CRPC) datasets from the West and East Stand Up to Cancer (SU2C) cohorts. Through this screening approach, we identified E2F8, a putative transcriptional repressor, as a TF consistently associated with poorer patient outcomes in both cohorts. Notably, E2F8 is highly expressed and active in AR-negative CRPC compared to AR-positive CRPC. Integrative profiling of E2F8 cistromes and transcriptomes in AR-negative CRPC cells revealed that E2F8 directly and non-canonically activates target oncogenes involved in cancer-associated pathways. To target E2F8 in CRPC, we employed the CRISPR/CasRx system to knockdown E2F8 mRNA, resulting in effective and specific downregulation of E2F8 and its target oncogenes, as well as significant growth inhibition in AR-negative CRPC in both cultured cells and xenograft models. Our findings identify and characterize E2F8 as a targetable transcriptional activator driving CRPC, particularly the growth of AR-negative CRPC.
{"title":"Integrative analysis identifies the atypical repressor E2F8 as a targetable transcriptional activator driving lethal prostate cancer","authors":"Furong Huang, Kexin Li, Zhong Chen, Zhifen Cui, William Hankey, Kun Fang, Jingyue Yan, Hongyan Wang, Victor X. Jin, Yizhou Dong, Qianben Wang","doi":"10.1038/s41388-024-03239-2","DOIUrl":"10.1038/s41388-024-03239-2","url":null,"abstract":"Acquired resistance to androgen receptor (AR)-targeted therapies underscores the need to identify alternative therapeutic targets for treating lethal prostate cancer. In this study, we evaluated the prognostic significance of 1635 human transcription factors (TFs) by analyzing castration-resistant prostate cancer (CRPC) datasets from the West and East Stand Up to Cancer (SU2C) cohorts. Through this screening approach, we identified E2F8, a putative transcriptional repressor, as a TF consistently associated with poorer patient outcomes in both cohorts. Notably, E2F8 is highly expressed and active in AR-negative CRPC compared to AR-positive CRPC. Integrative profiling of E2F8 cistromes and transcriptomes in AR-negative CRPC cells revealed that E2F8 directly and non-canonically activates target oncogenes involved in cancer-associated pathways. To target E2F8 in CRPC, we employed the CRISPR/CasRx system to knockdown E2F8 mRNA, resulting in effective and specific downregulation of E2F8 and its target oncogenes, as well as significant growth inhibition in AR-negative CRPC in both cultured cells and xenograft models. Our findings identify and characterize E2F8 as a targetable transcriptional activator driving CRPC, particularly the growth of AR-negative CRPC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 8","pages":"481-493"},"PeriodicalIF":6.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03239-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755365","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 : 2024-11-29DOI: 10.1038/s41388-024-03222-x
Keith S. Robinson, Peter Sennhenn, Daniel S. Yuan, Hai Liu, David Taddei, Yue Qian, Wei Luo
Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, also known as Bax Inhibitor-1 (BI-1), has been heavily researched for its cytoprotective functions. TMBIM6 functional diversity includes modulating cell survival, stress, metabolism, cytoskeletal dynamics, organelle function, regulating cytosolic acidification, calcium, and reactive oxygen species (ROS). Clinical research shows TMBIM6 plays a key role in many of the world’s top diseases/injuries (i.e., Alzheimer’s, Parkinson’s, diabetes, obesity, brain injury, liver disease, heart disease, aging, etc.), including cancer, where TMBIM6 expression impacts patient survival, chemoresistance, cancer progression, and metastasis. We show TMBIM6 is activated by, and undergoes, different conformational changes that dictate its function following a significant change in the cell’s IntraCellular Environment (ICE). TMBIM6 agonism, following ICE change, can help the cell overcome multiple stresses including toxin exposure, viral infection, wound healing, and excitotoxicity. However, in cancer cells TMBIM6 agonism results in rapid paraptotic induction irrespective of the cancer type, sub-type, genotype or phenotype. Furthermore, the level of TMBIM6 expression in cancer did not dictate the level of paraptotic induction; however, it did dictate the rate at which paraptosis occurred. TMBIM6 agonism did not induce paraptosis in cancer via canonical routes involving p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9. Instead, TMBIM6 agonism in cancer upregulates cytosolic Ca2+ and ROS, activates lysosome biogenesis, and induces paraptosis via ERAD II mechanisms. In xenograft models, we show TMBIM6 agonism induces rapid cancer cell death with no toxicity, even at high doses of TMBIM6 agonist (>450 mg/kg). In summary, this study shows TMBIM6’s functional diversity is only activated by severe ICE change in diseased/injured cells, highlighting its transformative potential as a therapeutic target across various diseases and injuries, including cancer.
{"title":"TMBIM6/BI-1 is an intracellular environmental regulator that induces paraptosis in cancer via ROS and Calcium-activated ERAD II pathways","authors":"Keith S. Robinson, Peter Sennhenn, Daniel S. Yuan, Hai Liu, David Taddei, Yue Qian, Wei Luo","doi":"10.1038/s41388-024-03222-x","DOIUrl":"10.1038/s41388-024-03222-x","url":null,"abstract":"Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, also known as Bax Inhibitor-1 (BI-1), has been heavily researched for its cytoprotective functions. TMBIM6 functional diversity includes modulating cell survival, stress, metabolism, cytoskeletal dynamics, organelle function, regulating cytosolic acidification, calcium, and reactive oxygen species (ROS). Clinical research shows TMBIM6 plays a key role in many of the world’s top diseases/injuries (i.e., Alzheimer’s, Parkinson’s, diabetes, obesity, brain injury, liver disease, heart disease, aging, etc.), including cancer, where TMBIM6 expression impacts patient survival, chemoresistance, cancer progression, and metastasis. We show TMBIM6 is activated by, and undergoes, different conformational changes that dictate its function following a significant change in the cell’s IntraCellular Environment (ICE). TMBIM6 agonism, following ICE change, can help the cell overcome multiple stresses including toxin exposure, viral infection, wound healing, and excitotoxicity. However, in cancer cells TMBIM6 agonism results in rapid paraptotic induction irrespective of the cancer type, sub-type, genotype or phenotype. Furthermore, the level of TMBIM6 expression in cancer did not dictate the level of paraptotic induction; however, it did dictate the rate at which paraptosis occurred. TMBIM6 agonism did not induce paraptosis in cancer via canonical routes involving p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9. Instead, TMBIM6 agonism in cancer upregulates cytosolic Ca2+ and ROS, activates lysosome biogenesis, and induces paraptosis via ERAD II mechanisms. In xenograft models, we show TMBIM6 agonism induces rapid cancer cell death with no toxicity, even at high doses of TMBIM6 agonist (>450 mg/kg). In summary, this study shows TMBIM6’s functional diversity is only activated by severe ICE change in diseased/injured cells, highlighting its transformative potential as a therapeutic target across various diseases and injuries, including cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 8","pages":"494-512"},"PeriodicalIF":6.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03222-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751359","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 : 2024-11-29DOI: 10.1038/s41388-024-03229-4
Dan Wu, Hua Tan, Weijun Su, Dongmei Cheng, Guanwen Wang, Juan Wang, Ding A. Ma, George M. Dong, Peiqing Sun
{"title":"Correction: MZF1 mediates oncogene-induced senescence by promoting the transcription of p16INK4A","authors":"Dan Wu, Hua Tan, Weijun Su, Dongmei Cheng, Guanwen Wang, Juan Wang, Ding A. Ma, George M. Dong, Peiqing Sun","doi":"10.1038/s41388-024-03229-4","DOIUrl":"10.1038/s41388-024-03229-4","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 4","pages":"272-275"},"PeriodicalIF":6.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03229-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755362","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 : 2024-11-26DOI: 10.1038/s41388-024-03230-x
Elisa Rodrigues Sousa, Simone de Brot, Eugenio Zoni, Soheila Zeinali, Andrea Brunello, Mario Scarpa, Marta De Menna, Federico La Manna, Allen Abey Alexander, Irena Klima, David W. Freeman, Brooke L. Gates, Domenico A. Cristaldi, Olivier T. Guenat, Boudewijn P. T. Kruithof, Benjamin T. Spike, Panagiotis Chouvardas, Marianna Kruithof-de Julio
CRIPTO (or CR-1 or TDGF1) is a protein that plays an active role in tumor initiation and progression. We have confirmed that increased expression of CRIPTO is associated with clinical and prostate-specific antigen (PSA) progression in human prostate tissues. Our approach involved gaining insight into the role of CRIPTO signaling in castration-resistant Nkx3.1-expressing cells (CARNs), targets for oncogenic transformation in prostate cancer (PCa), by integrating the existing Criptoflox/flox into CARNs model. The most aggressive stage was modeled using an inducible Cre under control of the Nkx3.1 promoter conferring Nkx3.1 inactivation and driving Pten inactivation, oncogenic Kras activation, and lineage tracing with yellow fluorescence protein (EYFP) upon induction. Our findings provide evidence that selective depletion of Cripto in epithelial cells in vivo reduced the invasive phenotype, particularly in more advanced tumor stages. Moreover, in vitro experiments with Cripto overexpression demonstrated alterations in the physical features of organoids, which correlated with increased tumorigenic activity. Transcriptomic analyses revealed a unique CRIPTO/MYC co-activation signature associated with PSA progression in a human PCa cohort. Taken together, our data highlights a role for CRIPTO in tumor invasiveness and progression, which carries implications for biomarkers and targeted therapies.
{"title":"CRIPTO’s multifaceted role in driving aggressive prostate cancer unveiled by in vivo, organoid, and patient data","authors":"Elisa Rodrigues Sousa, Simone de Brot, Eugenio Zoni, Soheila Zeinali, Andrea Brunello, Mario Scarpa, Marta De Menna, Federico La Manna, Allen Abey Alexander, Irena Klima, David W. Freeman, Brooke L. Gates, Domenico A. Cristaldi, Olivier T. Guenat, Boudewijn P. T. Kruithof, Benjamin T. Spike, Panagiotis Chouvardas, Marianna Kruithof-de Julio","doi":"10.1038/s41388-024-03230-x","DOIUrl":"10.1038/s41388-024-03230-x","url":null,"abstract":"CRIPTO (or CR-1 or TDGF1) is a protein that plays an active role in tumor initiation and progression. We have confirmed that increased expression of CRIPTO is associated with clinical and prostate-specific antigen (PSA) progression in human prostate tissues. Our approach involved gaining insight into the role of CRIPTO signaling in castration-resistant Nkx3.1-expressing cells (CARNs), targets for oncogenic transformation in prostate cancer (PCa), by integrating the existing Criptoflox/flox into CARNs model. The most aggressive stage was modeled using an inducible Cre under control of the Nkx3.1 promoter conferring Nkx3.1 inactivation and driving Pten inactivation, oncogenic Kras activation, and lineage tracing with yellow fluorescence protein (EYFP) upon induction. Our findings provide evidence that selective depletion of Cripto in epithelial cells in vivo reduced the invasive phenotype, particularly in more advanced tumor stages. Moreover, in vitro experiments with Cripto overexpression demonstrated alterations in the physical features of organoids, which correlated with increased tumorigenic activity. Transcriptomic analyses revealed a unique CRIPTO/MYC co-activation signature associated with PSA progression in a human PCa cohort. Taken together, our data highlights a role for CRIPTO in tumor invasiveness and progression, which carries implications for biomarkers and targeted therapies.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 7","pages":"462-475"},"PeriodicalIF":6.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03230-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731511","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 : 2024-11-23DOI: 10.1038/s41388-024-03234-7
Bowen Sun, Ge Wang, Guoyu Chen, Yingwen Zhang, Ru Yang, He Hua, Yanxin Li, Haizhong Feng
Inducing tumor cell differentiation is a promising strategy for treating malignant cancers, including glioma, yet the critical regulator(s) underlying glioma cell differentiation is poorly understood. Here, we identify G Protein Subunit Alpha O1 (GNAO1) as a critical regulator of neural differentiation of glioma stem-like cells (GSCs). GNAO1 expression was lower in gliomas than in normal neuronal tissues and high expression of GNAO1 correlated with a better prognosis. GNAO1 overexpression markedly promoted neural differentiation of GSCs, leading to decreased cell proliferation and colony formation. Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination. This ubiquitination resulted in the degradation of CREB and further reduced p300-mediated H3K27ac levels of the HES1 promoter. As a result, GNAO1 overexpression downregulated HES1 expression, which reinforced neuronal differentiation. In addition, knockdown of METTL3, a key writer of the N6-methyladenosine (m6A), enhanced GNAO1 mRNA stability. Treatment with GNAO1 adenovirus increased neuronal differentiation of tumor cells and reduced tumor cell proliferation in orthotopic GSC xenografts and temozolomide further enhanced GNAO1 adenovirus effects, resulting in extended animal survival. Our study presents that engineering GNAO1 overexpression-inducing neural differentiation of GSCs is a potential therapy strategy via synergistic inhibition of malignant proliferation and chemotherapy resistance.
{"title":"GNAO1 overexpression promotes neural differentiation of glioma stem-like cells and reduces tumorigenicity through TRIM21/CREB/HES1 axis","authors":"Bowen Sun, Ge Wang, Guoyu Chen, Yingwen Zhang, Ru Yang, He Hua, Yanxin Li, Haizhong Feng","doi":"10.1038/s41388-024-03234-7","DOIUrl":"10.1038/s41388-024-03234-7","url":null,"abstract":"Inducing tumor cell differentiation is a promising strategy for treating malignant cancers, including glioma, yet the critical regulator(s) underlying glioma cell differentiation is poorly understood. Here, we identify G Protein Subunit Alpha O1 (GNAO1) as a critical regulator of neural differentiation of glioma stem-like cells (GSCs). GNAO1 expression was lower in gliomas than in normal neuronal tissues and high expression of GNAO1 correlated with a better prognosis. GNAO1 overexpression markedly promoted neural differentiation of GSCs, leading to decreased cell proliferation and colony formation. Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination. This ubiquitination resulted in the degradation of CREB and further reduced p300-mediated H3K27ac levels of the HES1 promoter. As a result, GNAO1 overexpression downregulated HES1 expression, which reinforced neuronal differentiation. In addition, knockdown of METTL3, a key writer of the N6-methyladenosine (m6A), enhanced GNAO1 mRNA stability. Treatment with GNAO1 adenovirus increased neuronal differentiation of tumor cells and reduced tumor cell proliferation in orthotopic GSC xenografts and temozolomide further enhanced GNAO1 adenovirus effects, resulting in extended animal survival. Our study presents that engineering GNAO1 overexpression-inducing neural differentiation of GSCs is a potential therapy strategy via synergistic inhibition of malignant proliferation and chemotherapy resistance.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 7","pages":"450-461"},"PeriodicalIF":6.9,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03234-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695761","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 : 2024-11-22DOI: 10.1038/s41388-024-03212-z
Michael J. Schmidt, Amin Naghdloo, Rishvanth K. Prabakar, Mohamed Kamal, Radu Cadaneanu, Isla P. Garraway, Michael Lewis, Ana Aparicio, Amado Zurita-Saavedra, Paul Corn, Peter Kuhn, Kenneth J. Pienta, Sarah R. Amend, James Hicks
Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and are associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and the expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.
{"title":"Polyploid cancer cells reveal signatures of chemotherapy resistance","authors":"Michael J. Schmidt, Amin Naghdloo, Rishvanth K. Prabakar, Mohamed Kamal, Radu Cadaneanu, Isla P. Garraway, Michael Lewis, Ana Aparicio, Amado Zurita-Saavedra, Paul Corn, Peter Kuhn, Kenneth J. Pienta, Sarah R. Amend, James Hicks","doi":"10.1038/s41388-024-03212-z","DOIUrl":"10.1038/s41388-024-03212-z","url":null,"abstract":"Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and are associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and the expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 7","pages":"439-449"},"PeriodicalIF":6.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03212-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693257","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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