Pub Date : 2024-09-29DOI: 10.1038/s41388-024-03178-y
Hengjie Xu, Tuo Wang, Hongxu Nie, Qingyang Sun, Chi Jin, Sheng Yang, Zhihao Chen, Xiaowei Wang, Junwei Tang, Yifei Feng, Yueming Sun
Colorectal cancer (CRC) stands as the second most common cause of cancer-related mortality globally and p53, a widely recognized tumor suppressor, contributes to the development of CRC. Ubiquitin-specific protease 36 (USP36), belonging to the deubiquitinating enzyme family, is involved in tumor progression across multiple cancers. However, the underlying molecular mechanism in which USP36 regulates p53 signaling pathway in CRC is unclear. Here, our study revealed that USP36 was increased in CRC tissues and associated with unfavorable prognosis. Functionally, elevated USP36 could promote proliferation, migration, and invasion of CRC cells in vitro and in vivo. Mechanistically, USP36 could interact with and stabilize RBM28 via deubiquitination at K162 residue. Further, upregulated RBM28 could bind with p53 to suppress its transcriptional activity and therefore inactivate p53 signaling pathway. Collectively, our investigation identified the novel USP36/RBM28/p53 axis and its involvement in promoting cell proliferation and metastasis in CRC, which presents a promising therapeutic strategy for CRC treatment.
{"title":"USP36 promotes colorectal cancer progression through inhibition of p53 signaling pathway via stabilizing RBM28","authors":"Hengjie Xu, Tuo Wang, Hongxu Nie, Qingyang Sun, Chi Jin, Sheng Yang, Zhihao Chen, Xiaowei Wang, Junwei Tang, Yifei Feng, Yueming Sun","doi":"10.1038/s41388-024-03178-y","DOIUrl":"10.1038/s41388-024-03178-y","url":null,"abstract":"Colorectal cancer (CRC) stands as the second most common cause of cancer-related mortality globally and p53, a widely recognized tumor suppressor, contributes to the development of CRC. Ubiquitin-specific protease 36 (USP36), belonging to the deubiquitinating enzyme family, is involved in tumor progression across multiple cancers. However, the underlying molecular mechanism in which USP36 regulates p53 signaling pathway in CRC is unclear. Here, our study revealed that USP36 was increased in CRC tissues and associated with unfavorable prognosis. Functionally, elevated USP36 could promote proliferation, migration, and invasion of CRC cells in vitro and in vivo. Mechanistically, USP36 could interact with and stabilize RBM28 via deubiquitination at K162 residue. Further, upregulated RBM28 could bind with p53 to suppress its transcriptional activity and therefore inactivate p53 signaling pathway. Collectively, our investigation identified the novel USP36/RBM28/p53 axis and its involvement in promoting cell proliferation and metastasis in CRC, which presents a promising therapeutic strategy for CRC treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 47","pages":"3442-3455"},"PeriodicalIF":6.9,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03178-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351304","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 : 2024-09-28DOI: 10.1038/s41388-024-03155-5
Zhenqiang Sun, Pengyuan Dang, Yaxin Guo, Senbo Liu, Shengyun Hu, Haifeng Sun, Yanxin Xu, Wenkang Wang, Chen Chen, Jinbo Liu, Zhenyu Ji, Yang Liu, Junhong Hu
Tumor progression of colorectal cancer (CRC) seriously affects patient prognosis. For CRC patients with advanced-stage disease, it is still necessary to continuously explore more effective targeted therapeutic drugs. Circular RNAs (circRNAs) are involved in the regulation of tumor biology. We screened circAURKA, which was significantly highly expressed in CRC by previous high-throughput RNA sequencing. In vitro experiments were performed to investigate the effect of the circRNA on the proliferation and metastasis of HCT116 and SW480 cells. In addition, we used the EdU assay, Transwell assay, nude mouse xenograft tumor model and nude mouse tail vein metastasis model to examine the effect of circAURKA on the proliferation and metastasis of CRC. Mechanistically, fluorescent in situ hybridization (FISH), RNA pull-down, RNA immunoprecipitation (RIP), protein coimmunoprecipitation (co-IP) experiments and animal models were performed to confirm the underlying mechanisms of circAURKA. CircAURKA was significantly highly expressed in CRC tissues and colorectal cells and mainly present in the cytoplasm. The circRNA promoted the proliferation and metastasis of CRC cells in vitro and in vivo. In terms of the molecular mechanism, circAURKA inhibited the degradation of the CTNNB1 protein by promoting the interaction between ACLY and the CTNNB1 protein, thereby promoting the proliferation and metastasis of CRC cells. In addition, circAURKA stability was regulated by m6A methylation modification. This study revealed that circAURKA promoted the proliferation and metastasis of CRC by inhibiting CTNNB1 protein degradation, providing a basis for the development of targeted drugs to control CRC progression.
{"title":"Targeting CircAURKA prevents colorectal cancer progression via enhancing CTNNB1 protein degradation","authors":"Zhenqiang Sun, Pengyuan Dang, Yaxin Guo, Senbo Liu, Shengyun Hu, Haifeng Sun, Yanxin Xu, Wenkang Wang, Chen Chen, Jinbo Liu, Zhenyu Ji, Yang Liu, Junhong Hu","doi":"10.1038/s41388-024-03155-5","DOIUrl":"10.1038/s41388-024-03155-5","url":null,"abstract":"Tumor progression of colorectal cancer (CRC) seriously affects patient prognosis. For CRC patients with advanced-stage disease, it is still necessary to continuously explore more effective targeted therapeutic drugs. Circular RNAs (circRNAs) are involved in the regulation of tumor biology. We screened circAURKA, which was significantly highly expressed in CRC by previous high-throughput RNA sequencing. In vitro experiments were performed to investigate the effect of the circRNA on the proliferation and metastasis of HCT116 and SW480 cells. In addition, we used the EdU assay, Transwell assay, nude mouse xenograft tumor model and nude mouse tail vein metastasis model to examine the effect of circAURKA on the proliferation and metastasis of CRC. Mechanistically, fluorescent in situ hybridization (FISH), RNA pull-down, RNA immunoprecipitation (RIP), protein coimmunoprecipitation (co-IP) experiments and animal models were performed to confirm the underlying mechanisms of circAURKA. CircAURKA was significantly highly expressed in CRC tissues and colorectal cells and mainly present in the cytoplasm. The circRNA promoted the proliferation and metastasis of CRC cells in vitro and in vivo. In terms of the molecular mechanism, circAURKA inhibited the degradation of the CTNNB1 protein by promoting the interaction between ACLY and the CTNNB1 protein, thereby promoting the proliferation and metastasis of CRC cells. In addition, circAURKA stability was regulated by m6A methylation modification. This study revealed that circAURKA promoted the proliferation and metastasis of CRC by inhibiting CTNNB1 protein degradation, providing a basis for the development of targeted drugs to control CRC progression.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 46","pages":"3388-3401"},"PeriodicalIF":6.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03155-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351303","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 : 2024-09-28DOI: 10.1038/s41388-024-03172-4
Briana To, Carson Broeker, Jing-Ru Jhan, Jesus Garcia-Lerena, John Vusich, Rachel Rempel, Jonathan P. Rennhack, Daniel Hollern, Lauren Jackson, David Judah, Matt Swiatnicki, Evan Bylett, Rachel Kubiak, Jordan Honeysett, Joseph Nevins, Eran Andrechek
Development of breast cancer is linked to altered regulation of mammary gland developmental processes. A better understanding of normal mammary gland development can thus reveal possible mechanisms of how normal cells are re-programmed to become malignant. E2Fs 1-4 are part of the E2F transcription factor family with varied roles in mammary development, but little is known about the role of E2F5. A combination of scRNAseq and predictive signature tools demonstrated the presence of E2F5 in the mammary gland and showed changes in predicted activity during the various phases of mammary gland development. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors. Whole genome sequencing revealed significant intertumor heterogeneity. RNAseq and protein analysis identified altered levels of Cyclin D1, with similarities to MMTV-Neu tumors, suggesting that E2F5 conditional knockout mammary glands and tumors may be dependent on Cyclin D1. Transplantation of the tumors revealed metastases to lymph nodes that were enriched through serial transplantation in immune competent recipients. Based on these findings, we propose that loss of E2F5 leads to altered regulation of Cyclin D1, which facilitates the development of metastatic mammary tumors after long latency. More importantly, this study demonstrates that conditional loss of E2F5 in the mammary gland leads to tumor formation, revealing its role as a transcription factor regulating a network of genes that normally result in a tumor suppressor function.
{"title":"Insight into mammary gland development and tumor progression in an E2F5 conditional knockout mouse model","authors":"Briana To, Carson Broeker, Jing-Ru Jhan, Jesus Garcia-Lerena, John Vusich, Rachel Rempel, Jonathan P. Rennhack, Daniel Hollern, Lauren Jackson, David Judah, Matt Swiatnicki, Evan Bylett, Rachel Kubiak, Jordan Honeysett, Joseph Nevins, Eran Andrechek","doi":"10.1038/s41388-024-03172-4","DOIUrl":"10.1038/s41388-024-03172-4","url":null,"abstract":"Development of breast cancer is linked to altered regulation of mammary gland developmental processes. A better understanding of normal mammary gland development can thus reveal possible mechanisms of how normal cells are re-programmed to become malignant. E2Fs 1-4 are part of the E2F transcription factor family with varied roles in mammary development, but little is known about the role of E2F5. A combination of scRNAseq and predictive signature tools demonstrated the presence of E2F5 in the mammary gland and showed changes in predicted activity during the various phases of mammary gland development. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors. Whole genome sequencing revealed significant intertumor heterogeneity. RNAseq and protein analysis identified altered levels of Cyclin D1, with similarities to MMTV-Neu tumors, suggesting that E2F5 conditional knockout mammary glands and tumors may be dependent on Cyclin D1. Transplantation of the tumors revealed metastases to lymph nodes that were enriched through serial transplantation in immune competent recipients. Based on these findings, we propose that loss of E2F5 leads to altered regulation of Cyclin D1, which facilitates the development of metastatic mammary tumors after long latency. More importantly, this study demonstrates that conditional loss of E2F5 in the mammary gland leads to tumor formation, revealing its role as a transcription factor regulating a network of genes that normally result in a tumor suppressor function.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 46","pages":"3402-3415"},"PeriodicalIF":6.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03172-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351302","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}
Dysregulated N6-methyladenosine (m6A) modification has been associated with breast cancer pathogenesis. Hypoxia which characterizes solid tumors is known to reprogram the m6A epitranscriptome, but the underlying mechanisms of how this process contributes to breast cancer progression remain poorly understood. Through integrative analyses of m6A-RIP sequencing and RNA sequencing databases, we reveal a cluster of mRNAs with upregulated m6A methylation and expression under hypoxia, that are enriched by many oncogenic pathways, including PI3K–Akt signaling. Furthermore, we identify the mRNA, RIPOR3, as a target of METTL3-mediated m6A methylation in response to hypoxia. We find that m6A methylation stabilizes RIPOR3, increasing its protein expression in a METTL3 catalytic activity-dependent manner, and consequently driving breast tumor growth and metastasis. RIPOR3 is found to be overexpressed in breast cancer cell lines and tumor tissues from breast cancer patients, in whom elevated RIPOR3 is associated with a worse prognosis. Mechanistically, we show that RIPOR3 interacts with EGFR and is essential for the PI3K–Akt pathway activation. In conclusion, we identify RIPOR3 as a hypoxia-stabilized oncogenic driver via METTL3-mediated m6A methylation, thus provide a potential therapeutic target for breast cancer.
{"title":"Hypoxic stabilization of RIPOR3 mRNA via METTL3-mediated m6A methylation drives breast cancer progression and metastasis","authors":"Jingjing Xiong, Zirui Zhou, Yulong Jiang, Qifang Li, Zuhan Geng, Jiahao Guo, Chaojun Yan, Jing Zhang","doi":"10.1038/s41388-024-03180-4","DOIUrl":"10.1038/s41388-024-03180-4","url":null,"abstract":"Dysregulated N6-methyladenosine (m6A) modification has been associated with breast cancer pathogenesis. Hypoxia which characterizes solid tumors is known to reprogram the m6A epitranscriptome, but the underlying mechanisms of how this process contributes to breast cancer progression remain poorly understood. Through integrative analyses of m6A-RIP sequencing and RNA sequencing databases, we reveal a cluster of mRNAs with upregulated m6A methylation and expression under hypoxia, that are enriched by many oncogenic pathways, including PI3K–Akt signaling. Furthermore, we identify the mRNA, RIPOR3, as a target of METTL3-mediated m6A methylation in response to hypoxia. We find that m6A methylation stabilizes RIPOR3, increasing its protein expression in a METTL3 catalytic activity-dependent manner, and consequently driving breast tumor growth and metastasis. RIPOR3 is found to be overexpressed in breast cancer cell lines and tumor tissues from breast cancer patients, in whom elevated RIPOR3 is associated with a worse prognosis. Mechanistically, we show that RIPOR3 interacts with EGFR and is essential for the PI3K–Akt pathway activation. In conclusion, we identify RIPOR3 as a hypoxia-stabilized oncogenic driver via METTL3-mediated m6A methylation, thus provide a potential therapeutic target for breast cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 47","pages":"3426-3441"},"PeriodicalIF":6.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351301","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 : 2024-09-26DOI: 10.1038/s41388-024-03177-z
Foram Dave, Kevin Herrera, Alex Lockley, Laurien L. van de Weijer, Summer Henderson, Agbolahan A. Sofela, Laura Hook, Claire L. Adams, Emanuela Ercolano, David A. Hilton, Emmanuel A. Maze, Kathreena M. Kurian, Sylwia Ammoun, C. Oliver Hanemann
{"title":"Correction: Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours","authors":"Foram Dave, Kevin Herrera, Alex Lockley, Laurien L. van de Weijer, Summer Henderson, Agbolahan A. Sofela, Laura Hook, Claire L. Adams, Emanuela Ercolano, David A. Hilton, Emmanuel A. Maze, Kathreena M. Kurian, Sylwia Ammoun, C. Oliver Hanemann","doi":"10.1038/s41388-024-03177-z","DOIUrl":"10.1038/s41388-024-03177-z","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 41","pages":"3080-3080"},"PeriodicalIF":6.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03177-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351368","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 : 2024-09-25DOI: 10.1038/s41388-024-03171-5
Chi Zhang, Yu-Jing Lu, Mei Wang, Bingjie Chen, Feifei Xiong, Costas Mitsopoulos, Olivia Rossanese, Xiuling Li, Paul A. Clarke
RNA editing is a crucial post-transcriptional process that influences gene expression and increases the diversity of the proteome as a result of amino acid substitution. Recently, the APOBEC3 family has emerged as a significant player in this mechanism, with APOBEC3A (A3A) having prominent roles in base editing during immune and stress responses. APOBEC3B (A3B), another family member, has gained attention for its potential role in generating genomic DNA mutations in breast cancer. In this study, we coupled an inducible expression cell model with a novel methodology for identifying differential variants in RNA (DVRs) to map A3B-mediated RNA editing sites in a breast cancer cell model. Our findings indicate that A3B engages in selective RNA editing including targeting NEAT1 and MALAT1 long non-coding RNAs that are often highly expressed in tumour cells. Notably, the binding of these RNAs sequesters A3B and suppresses global A3B activity against RNA and DNA. Release of A3B from NEAT1/MALAT1 resulted in increased A3B activity at the expense of A3A activity suggesting a regulatory feedback loop between the two family members. This research substantially advances our understanding of A3B’s role in RNA editing, its mechanistic underpinnings, and its potential relevance in the pathogenesis of breast cancer.
{"title":"Characterisation of APOBEC3B-Mediated RNA editing in breast cancer cells reveals regulatory roles of NEAT1 and MALAT1 lncRNAs","authors":"Chi Zhang, Yu-Jing Lu, Mei Wang, Bingjie Chen, Feifei Xiong, Costas Mitsopoulos, Olivia Rossanese, Xiuling Li, Paul A. Clarke","doi":"10.1038/s41388-024-03171-5","DOIUrl":"10.1038/s41388-024-03171-5","url":null,"abstract":"RNA editing is a crucial post-transcriptional process that influences gene expression and increases the diversity of the proteome as a result of amino acid substitution. Recently, the APOBEC3 family has emerged as a significant player in this mechanism, with APOBEC3A (A3A) having prominent roles in base editing during immune and stress responses. APOBEC3B (A3B), another family member, has gained attention for its potential role in generating genomic DNA mutations in breast cancer. In this study, we coupled an inducible expression cell model with a novel methodology for identifying differential variants in RNA (DVRs) to map A3B-mediated RNA editing sites in a breast cancer cell model. Our findings indicate that A3B engages in selective RNA editing including targeting NEAT1 and MALAT1 long non-coding RNAs that are often highly expressed in tumour cells. Notably, the binding of these RNAs sequesters A3B and suppresses global A3B activity against RNA and DNA. Release of A3B from NEAT1/MALAT1 resulted in increased A3B activity at the expense of A3A activity suggesting a regulatory feedback loop between the two family members. This research substantially advances our understanding of A3B’s role in RNA editing, its mechanistic underpinnings, and its potential relevance in the pathogenesis of breast cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 46","pages":"3366-3377"},"PeriodicalIF":6.9,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03171-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351367","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 : 2024-09-25DOI: 10.1038/s41388-024-03176-0
Taner Duysak, Kwangsoo Kim, Misun Yun, Jae-Ho Jeong, Hyon E. Choy
Amino acid deprivation, particularly of nonessential amino acids that can be synthesized by normal cells but not by cancer cells with specific defects in the biosynthesis pathway, has emerged as a potential strategy in cancer therapeutics. In normal cells, arginine is synthesized from citrulline in two steps via two enzymes: argininosuccinate synthetase (ASS1) and argininosuccinate lyase. Several cancer cells exhibit arginine auxotrophy due to the loss or down-regulation of ASS1. These cells undergo starvation-induced cell death in the presence of arginine-degrading enzymes such as arginine deaminase (ADI). Thus, ADI has emerged as a potential therapeutic in cancer therapy. However, the use of ADI has two major disadvantages: ADI of bacterial origin is strongly antigenic in mammals, and ADI has a short circulation half-life (∼5 h). In this study, we engineered tumor-targeting Salmonella Gallinarum to express and secrete ADI and deployed this strain into mice implanted with ASS1-defective mouse colorectal cancer (CT26) through an intravenous route. A notable antitumor effect was observed, suggesting that the disadvantages were overcome as ADI was expressed constitutively by tumor-targeting bacteria. A combination with chloroquine, which inhibits the induction of autophagy, further enhanced the effect.
氨基酸匮乏，尤其是正常细胞能合成但生物合成途径存在特定缺陷的癌细胞不能合成的非必需氨基酸，已成为癌症治疗的一种潜在策略。在正常细胞中，精氨酸通过两种酶分两步从瓜氨酸合成：精氨酸琥珀酸合成酶（ASS1）和精氨酸琥珀酸裂解酶。由于 ASS1 的缺失或下调，一些癌细胞表现出精氨酸营养不良。在精氨酸脱氨酶（ADI）等精氨酸降解酶的作用下，这些细胞会发生饥饿诱导的细胞死亡。因此，ADI 已成为癌症治疗的一种潜在疗法。然而，使用 ADI 有两大缺点：源于细菌的 ADI 在哺乳动物体内具有很强的抗原性，而且 ADI 在血液循环中的半衰期很短（5 小时）。在本研究中，我们设计了能表达和分泌 ADI 的肿瘤靶向胆囊沙门氏菌，并将该菌株通过静脉注射途径植入 ASS1 基因缺陷小鼠结直肠癌（CT26）。观察到了显著的抗肿瘤效果，这表明肿瘤靶向细菌组成型表达的 ADI 克服了其缺点。与可抑制自噬诱导的氯喹联合使用可进一步增强效果。表达精氨酸脱氨酶（ADI）的加里纳氏沙门氏菌对精氨酸依赖性原位肿瘤的抗癌作用。
{"title":"Enhanced anti-cancer efficacy of arginine deaminase expressed by tumor-seeking Salmonella Gallinarum","authors":"Taner Duysak, Kwangsoo Kim, Misun Yun, Jae-Ho Jeong, Hyon E. Choy","doi":"10.1038/s41388-024-03176-0","DOIUrl":"10.1038/s41388-024-03176-0","url":null,"abstract":"Amino acid deprivation, particularly of nonessential amino acids that can be synthesized by normal cells but not by cancer cells with specific defects in the biosynthesis pathway, has emerged as a potential strategy in cancer therapeutics. In normal cells, arginine is synthesized from citrulline in two steps via two enzymes: argininosuccinate synthetase (ASS1) and argininosuccinate lyase. Several cancer cells exhibit arginine auxotrophy due to the loss or down-regulation of ASS1. These cells undergo starvation-induced cell death in the presence of arginine-degrading enzymes such as arginine deaminase (ADI). Thus, ADI has emerged as a potential therapeutic in cancer therapy. However, the use of ADI has two major disadvantages: ADI of bacterial origin is strongly antigenic in mammals, and ADI has a short circulation half-life (∼5 h). In this study, we engineered tumor-targeting Salmonella Gallinarum to express and secrete ADI and deployed this strain into mice implanted with ASS1-defective mouse colorectal cancer (CT26) through an intravenous route. A notable antitumor effect was observed, suggesting that the disadvantages were overcome as ADI was expressed constitutively by tumor-targeting bacteria. A combination with chloroquine, which inhibits the induction of autophagy, further enhanced the effect.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 46","pages":"3378-3387"},"PeriodicalIF":6.9,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351300","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 : 2024-09-22DOI: 10.1038/s41388-024-03170-6
Rosa Bordone, Devon Michael Ivy, Rodrigo D’Amico, Martina Barba, Miriam Gaggianesi, Fiorella Di Pastena, Bianca Cesaro, Francesca Bufalieri, Alessio Balzerano, Enrico De Smaele, Giuseppe Giannini, Lucia Di Marcotullio, Alessandro Fatica, Giorgio Stassi, Laura Di Magno, Sonia Coni, Gianluca Canettieri
The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment.
{"title":"MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation","authors":"Rosa Bordone, Devon Michael Ivy, Rodrigo D’Amico, Martina Barba, Miriam Gaggianesi, Fiorella Di Pastena, Bianca Cesaro, Francesca Bufalieri, Alessio Balzerano, Enrico De Smaele, Giuseppe Giannini, Lucia Di Marcotullio, Alessandro Fatica, Giorgio Stassi, Laura Di Magno, Sonia Coni, Gianluca Canettieri","doi":"10.1038/s41388-024-03170-6","DOIUrl":"10.1038/s41388-024-03170-6","url":null,"abstract":"The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 46","pages":"3349-3365"},"PeriodicalIF":6.9,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03170-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292689","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}
High-grade serous ovarian cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to ferroptosis, as shown by increased PTGS2 expression (a ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of ferroptosis and suggest targeting SGK1 alongside ferroptosis pathways as a potential therapeutic strategy for HGSOC patients.
{"title":"SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways","authors":"Xiaolin Sang, Jiaxin Han, Zhaojing Wang, Weiji Cai, Xingming Liao, Zhuolin Kong, Zhijie Yu, Hailing Cheng, Pixu Liu","doi":"10.1038/s41388-024-03173-3","DOIUrl":"10.1038/s41388-024-03173-3","url":null,"abstract":"High-grade serous ovarian cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to ferroptosis, as shown by increased PTGS2 expression (a ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of ferroptosis and suggest targeting SGK1 alongside ferroptosis pathways as a potential therapeutic strategy for HGSOC patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 45","pages":"3335-3347"},"PeriodicalIF":6.9,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03173-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292690","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 : 2024-09-20DOI: 10.1038/s41388-024-03165-3
Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, André Mateus, Maréne Landström
TGFβ potently modifies the extracellular matrix (ECM), which is thought to favor tumor cell invasion. However, the mechanism whereby the cancer cells employ the ECM proteins to facilitate their motility is largely unknown. In this study we used RNA-seq and proteomic analysis to examine the proteins secreted by castration-resistant prostate cancer (CRPC) cells upon TGFβ treatment and found that thrombospondin 1 (THBS1) was observed to be one of the predominant proteins. The CRISPR Cas9, or siRNA techniques was used to downregulate TGFβ type I receptor (TβRI) to interfere with TGFβ signaling in various cancer cells in vitro. The interaction of ECM proteins with the TβRI in the migratory prostate cancer cells in response to TGFβ1 was demonstrated by several different techniques to reveal that THBS1 mediates cell migration by interacting with integrin subunit alpha V (ITGAV) and TβRI. Deletion of TβRI or THBS1 in cancer cells prevented their migration and invasion. THBS1 belongs to a group of tumorigenic ECM proteins induced via TGFβ signaling in CRPC cells, and high expression of THBS1 in human prostate cancer tissues correlated with the degree of malignancy. TGFβ-induced production of THBS1 through TβRI facilitates the invasion and metastasis of CRPC cells as shown in vivo xenograft animal experiments.
{"title":"The TβRI promotes migration and metastasis through thrombospondin 1 and ITGAV in prostate cancer cells","authors":"Yabing Mu, Anders Wallenius, Guangxiang Zang, Shaochun Zhu, Stina Rudolfsson, Karthik Aripaka, Anders Bergh, André Mateus, Maréne Landström","doi":"10.1038/s41388-024-03165-3","DOIUrl":"10.1038/s41388-024-03165-3","url":null,"abstract":"TGFβ potently modifies the extracellular matrix (ECM), which is thought to favor tumor cell invasion. However, the mechanism whereby the cancer cells employ the ECM proteins to facilitate their motility is largely unknown. In this study we used RNA-seq and proteomic analysis to examine the proteins secreted by castration-resistant prostate cancer (CRPC) cells upon TGFβ treatment and found that thrombospondin 1 (THBS1) was observed to be one of the predominant proteins. The CRISPR Cas9, or siRNA techniques was used to downregulate TGFβ type I receptor (TβRI) to interfere with TGFβ signaling in various cancer cells in vitro. The interaction of ECM proteins with the TβRI in the migratory prostate cancer cells in response to TGFβ1 was demonstrated by several different techniques to reveal that THBS1 mediates cell migration by interacting with integrin subunit alpha V (ITGAV) and TβRI. Deletion of TβRI or THBS1 in cancer cells prevented their migration and invasion. THBS1 belongs to a group of tumorigenic ECM proteins induced via TGFβ signaling in CRPC cells, and high expression of THBS1 in human prostate cancer tissues correlated with the degree of malignancy. TGFβ-induced production of THBS1 through TβRI facilitates the invasion and metastasis of CRPC cells as shown in vivo xenograft animal experiments.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 45","pages":"3321-3334"},"PeriodicalIF":6.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03165-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292691","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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