{"title":"A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer.","authors":"Jingtao Wang, Fan Yang, Yurou Chen, Yuzhu Xing, Juyuan Huang, Jing Cao, Jiaqiang Xiong, Yanyan Liu, Qiuyan Zhao, Manwen Luo, Jie Xiong, Guanlan Fan, Qiongying Lyu, Feng Li, Wei Zhang","doi":"10.1038/s41388-025-03342-y","DOIUrl":"https://doi.org/10.1038/s41388-025-03342-y","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) are closely associated with drug resistance and recurrence in ovarian cancer patients. Although leptin is a high-risk factor for ovarian cancer and promotes stemness maintenance, a therapeutic strategy that counteracts the downstream signaling pathway of leptin remains elusive. Herein, the deubiquitinase OTUD1 was identified as a critical regulator of leptin in maintaining OCSCs properties. Mechanistically, leptin treatment significantly increased the chromatin enrichment of the transcription factor c-Jun, including the OTUD1 gene enhancer, which was sufficient to increase the OTUD1 protein level and subsequently cause OTUD1 aggresome formation, ASK1 recruitment and JNK/c-Jun pathway activation. The resultant positive feedback loop of c-Jun and OTUD1 was required for OCSCs stemness maintenance. Notably, the disruption of the positive feedback loop by targeting c-Jun or ASK1/JNK with T-5224, selonsertib, or ibrutinib markedly inhibited the leptin-induced stemness maintenance of OCSCs and tumorigenicity. Our findings reveal a crucial mechanism for leptin-mediated stemness maintenance and indicate that targeting c-Jun or the identified positive feedback loop has translational potential for ovarian cancer patients.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663732","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}
OncogenePub Date : 2025-03-18DOI: 10.1038/s41388-025-03326-y
Aurora Taira, Mervi Aavikko, Riku Katainen, Eevi Kaasinen, Niko Välimäki, Janne Ravantti, Ari Ristimäki, Toni T Seppälä, Laura Renkonen-Sinisalo, Anna Lepistö, Kyösti Tahkola, Anne Mattila, Selja Koskensalo, Jukka-Pekka Mecklin, Jan Böhm, Jesper Bertram Bramsen, Claus Lindbjerg Andersen, Kimmo Palin, Kristiina Rajamäki, Lauri A Aaltonen
{"title":"Comprehensive metabolomic and epigenomic characterization of microsatellite stable BRAF-mutated colorectal cancer.","authors":"Aurora Taira, Mervi Aavikko, Riku Katainen, Eevi Kaasinen, Niko Välimäki, Janne Ravantti, Ari Ristimäki, Toni T Seppälä, Laura Renkonen-Sinisalo, Anna Lepistö, Kyösti Tahkola, Anne Mattila, Selja Koskensalo, Jukka-Pekka Mecklin, Jan Böhm, Jesper Bertram Bramsen, Claus Lindbjerg Andersen, Kimmo Palin, Kristiina Rajamäki, Lauri A Aaltonen","doi":"10.1038/s41388-025-03326-y","DOIUrl":"https://doi.org/10.1038/s41388-025-03326-y","url":null,"abstract":"<p><p>Oncogenic codon V600E mutations of the BRAF gene affect 10-15% of colorectal cancers, resulting in activation of the MAPK/ERK signaling pathway and increased cell proliferation and survival. BRAF-mutated colorectal tumors are often microsatellite unstable and characterized by high DNA methylation levels. However, the mechanistic link between BRAF mutations and hypermethylation remains controversial. Understanding this link, particularly in microsatellite stable tumors is of great interest as these often show poor survival. We characterized the metabolomic, epigenetic and transcriptomic patterns of altogether 39 microsatellite stable BRAF-mutated colorectal cancers. Metabolomic analysis of tumor tissue showed low levels of vitamin C and its metabolites in BRAF-mutated tumors. Gene expression analysis indicated dysregulation of vitamin C antioxidant activity in these lesions. As vitamin C is an important cofactor for the activity of TET DNA demethylase enzymes, low vitamin C levels could directly contribute to the high methylation levels in these tumors by decreasing enzymatic TET activity. Vitamin C transporter gene SLC23A1 expression, as well as vitamin C metabolite levels, were inversely correlated with DNA methylation levels. This work proposes a new mechanistic link between BRAF mutations and hypermethylation, inspiring further work on the role of vitamin C in the genesis of BRAF-mutated colorectal cancer.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656855","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}
{"title":"A urine DNA methylation assay for early detection of renal cancer.","authors":"Tongshuai Shi, Hanzhong Chen, Zhifeng Wang, Hong Wang, Cheng Peng, Shang Huang, Ying Wen, Xiaoyong Pu, Zhixin Liang, Jianmei Zhong, Lingdian Wang, Xiaoxin Liang, Wei Wei, Teng Li, Jiaxin Chen, Zhiwei Chen, Xin Ma, Weimei Ruan, Jian-Bing Fan, Degang Ding, Jiumin Liu, Xu Zhang, Qingbo Huang","doi":"10.1038/s41388-024-03268-x","DOIUrl":"https://doi.org/10.1038/s41388-024-03268-x","url":null,"abstract":"<p><p>Renal cancer (RC) is the most lethal urological malignancy with 30% late diagnosis. Over 50% RCs are asymptomatic and discovered incidentally. Current RC detection relies on imaging while it lacks satisfactory sensitivity for detecting small-size tumors. A sensitive and robust diagnostic tool is needed to facilitate standardized RC early detection. Herein, we performed genome-wide methylation sequencing on both tissues and urine samples for RC DNA methylation makers discovery and developed a PCR-based RC early detector (RED) using a cohort of 93 RC and 35 non-RC urine samples. RED further achieved sensitivities of 82.2% and 80.7%, and specificities of 77.1% and 75% in a testing cohort (90 RC vs. 35 non-RC) and a validation cohort (119 RC vs. 48 non-RC), respectively. Importantly, RED exhibited 89.5% sensitivity for tumors in diameter <2 cm. It can detect 83.6% clear cell renal cell carcinoma, 75.0% of translocational renal cell carcinoma, 100% of primitive neuroectodermal tumors, renal malignant masenchymomas and mucinous tubular and spindle cell carcinoma. RED showed promising performance for RC detection with early stage and small size and have potential to be used in conjunction with imaging.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649595","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}
OncogenePub Date : 2025-03-17DOI: 10.1038/s41388-025-03349-5
Dong Joon Kim, Yong Weon Yi, Zigang Dong, Yeon-Sun Seong
{"title":"Therapeutic implication of oxidative stress-induced growth inhibitor 1 (OSGIN1) in cancer.","authors":"Dong Joon Kim, Yong Weon Yi, Zigang Dong, Yeon-Sun Seong","doi":"10.1038/s41388-025-03349-5","DOIUrl":"https://doi.org/10.1038/s41388-025-03349-5","url":null,"abstract":"<p><p>Oxidative stress is an imbalance of free radicals and antioxidants in redox signaling that regulate various pathogenesis and cellular functions. Although advances in technology provide further knowledge for biomarkers and potential therapeutic targets of oxidative stress, it is still needed to validate them to apply in clinical relevance, diagnostics, and therapeutics. With these backgrounds, a clinical understanding of biomarkers and molecular mechanisms has been emphasized. In this review, we describe oxidative stress-induced growth inhibitor 1 (OSGIN1), an oxidative stress response protein. Previous findings have provided evidence implicating the function of oxidative stress-dependent and -independent response in numerous chronic diseases and cancers. However, the functions and roles of OSGIN1 in tumorigenesis have not been appreciated yet. We highlight the cellular processes and functions dependent on the expression of OSGIN1 isoforms as well as the regulation of its expression by various cellular signaling pathways, especially in cancer. This review will provide an overview of the clinical significance and molecular mechanisms of OSGIN1.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649696","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}
{"title":"SPOP/NOLC1/B4GALT1 signaling axis enhances paclitaxel resistance in endometrial cancer by inducing O-dysglycosylation.","authors":"Fengguang Zhai, Yuxuan Li, Jingfei Zheng, Chunhong Yan, Shuyan Wang, Weili Yang, Jiabei Jin, Xia Luo, Ziqing Zhan, Jiaxin Shi, Siyuan Wang, Yan Lin, Lili Kong, Yidong Ge, Haoyun Wang, Meng Ye, Xiaofeng Jin","doi":"10.1038/s41388-025-03347-7","DOIUrl":"https://doi.org/10.1038/s41388-025-03347-7","url":null,"abstract":"<p><p>The effective treatment of paclitaxel-resistant patients remains a major challenge. We found that nucleolar and coiled body phosphoprotein 1 (NOLC1) was highly expressed in the paclitaxel-resistant endometrial cancer (ECa) cells and pathological tissue of ECa patients, which could promote the occurrence and progression of ECa cells. Mechanistically, we confirmed that the E3 ubiquitin ligase substrate-binding adaptor SPOP mediates the ubiquitination and degradation of NOLC1, thereby maintaining normal protein levels. However, ECa-associated SPOP mutants abrogated the binding and ubiquitination of NOLC1, resulting in the accumulation of NOLC1, and ultimately promoting the proliferation, migration, and invasion of ECa cells. In addition, we demonstrated that NOLC1 could act as a transcriptional factor to activate the transcriptional expression of B4GALT1, ultimately leading to abnormal glycosylation metabolism. Moreover, knockdown of B4GALT1 can partly counteract the cancer-promoting effect caused by the overexpression of NOLC1 in vitro and in vivo. Based on these findings, an O-glycosylation inhibitor combined with paclitaxel could effectively improve the sensitivity of paclitaxel-resistant cells. In summary, we found that SPOP can negatively regulate the NOLC1-B4GALT1 signaling axis in ECa, whereas ECa-associated SPOP mutants lead to abnormal activation of this signaling axis, leading to glycosylation metabolism disorders. In addition, paclitaxel combined with B4GALT1-KD or glycosylation inhibitors can significantly inhibit the growth of paclitaxel-resistant endometrial cancer cells.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649692","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}
OncogenePub Date : 2025-03-17DOI: 10.1038/s41388-025-03345-9
Allyson E. Koyen, Matthew Z. Madden, Dongkyoo Park, Elizabeth V. Minten, Priya Kapoor-Vazirani, Erica Werner, Neil T. Pfister, Ramona Haji-Seyed-Javadi, Hui Zhang, Jie Xu, Nikita Deng, Duc M. Duong, Turner J. Pecen, Zoë Frazier, Zachary D. Nagel, Jean-Bernard Lazaro, Kent W. Mouw, Nicholas T. Seyfried, Carlos S. Moreno, Taofeek K. Owonikoko, Xingming Deng, David S. Yu
{"title":"Correction: EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair","authors":"Allyson E. Koyen, Matthew Z. Madden, Dongkyoo Park, Elizabeth V. Minten, Priya Kapoor-Vazirani, Erica Werner, Neil T. Pfister, Ramona Haji-Seyed-Javadi, Hui Zhang, Jie Xu, Nikita Deng, Duc M. Duong, Turner J. Pecen, Zoë Frazier, Zachary D. Nagel, Jean-Bernard Lazaro, Kent W. Mouw, Nicholas T. Seyfried, Carlos S. Moreno, Taofeek K. Owonikoko, Xingming Deng, David S. Yu","doi":"10.1038/s41388-025-03345-9","DOIUrl":"10.1038/s41388-025-03345-9","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 13","pages":"928-930"},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03345-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649601","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}
OncogenePub Date : 2025-03-16DOI: 10.1038/s41388-025-03337-9
Xiaoming Bai, Tinghong Duan, Jiaofang Shao, Yutong Zhang, Guangyuan Xing, Jie Wang, Xue Liu, Min Wang, Yuanqiao He, Hai Wang, Zhi-Yuan Zhang, Min Ni, Jin-Yong Zhou, Jinshun Pan
{"title":"CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis.","authors":"Xiaoming Bai, Tinghong Duan, Jiaofang Shao, Yutong Zhang, Guangyuan Xing, Jie Wang, Xue Liu, Min Wang, Yuanqiao He, Hai Wang, Zhi-Yuan Zhang, Min Ni, Jin-Yong Zhou, Jinshun Pan","doi":"10.1038/s41388-025-03337-9","DOIUrl":"10.1038/s41388-025-03337-9","url":null,"abstract":"<p><p>Chemoresistance poses a significant challenge in colorectal cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited ferroptosis associated with multidrug resistance, and the ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for cancer treatment to overcome drug resistance in the future.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634374","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}
OncogenePub Date : 2025-03-13DOI: 10.1038/s41388-025-03331-1
Bangting Wang, Shijie Zhang, Yumeng Guo, Wenqing Gao, Hao Wu, Jiankun Wang, Yan Wang, Chunming Tang, Li Liu
{"title":"CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis","authors":"Bangting Wang, Shijie Zhang, Yumeng Guo, Wenqing Gao, Hao Wu, Jiankun Wang, Yan Wang, Chunming Tang, Li Liu","doi":"10.1038/s41388-025-03331-1","DOIUrl":"10.1038/s41388-025-03331-1","url":null,"abstract":"Chromobox homolog 2 (CBX2), a component of the polycomb repressive complex 1, is overexpressed in various cancers, but its specific role in colorectal cancer (CRC) is not fully understood. This study aimed to characterize the functional and regulatory roles of CBX2 in CRC. Tissue microarray analysis revealed the elevated CBX2 levels in tumor compared to adjacent normal tissues, which is significantly correlated with poor prognosis. Gain and loss of function studies demonstrated that CBX2 significantly promoted CRC progression and chemoresistance in cell lines, patient-derived CRC organoids and xenografts. In the AOM/DSS mouse model, treatment with the innovatively-developed cy5-PBAE/siCBX2 nanoparticle significantly reduced tumor aggressiveness. Mechanistic studies unveiled that the transcription factor RUNX1 is the positive regulator of CBX2. RNA-seq, ATAC-seq and CUT & RUN results indicated CBX2 knockdown induced epigenetic changes, especially alterations in chromatin accessibility. Moreover, we further identified MAP4K1 as a target gene of RUNX1-CBX2, with significant clinical and prognostic relevance in CRC. Collectively, these findings suggest the pivotal role of RUNX1-CBX2-MAP4K1 axis in CRC progression and underscore CBX2 as a promising biomarker and therapeutic target.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 13","pages":"909-926"},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625583","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}
OncogenePub Date : 2025-03-13DOI: 10.1038/s41388-025-03332-0
Daniel Greiner, Qian Xue, Trinity Qa Waddell, Elena Kurudza, Piyush Chaudhary, Rachel L Belote, Gianpietro Dotti, Robert L Judson-Torres, Melissa Q Reeves, Samuel H Cheshier, Minna Roh-Johnson
{"title":"Human CSPG4-targeting CAR-macrophages inhibit melanoma growth.","authors":"Daniel Greiner, Qian Xue, Trinity Qa Waddell, Elena Kurudza, Piyush Chaudhary, Rachel L Belote, Gianpietro Dotti, Robert L Judson-Torres, Melissa Q Reeves, Samuel H Cheshier, Minna Roh-Johnson","doi":"10.1038/s41388-025-03332-0","DOIUrl":"10.1038/s41388-025-03332-0","url":null,"abstract":"<p><p>Approximately half of melanoma patients relapse or fail to respond to current standards of care, highlighting the need for new treatment options. Engineering T-cells with chimeric antigen receptors (CARs) has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. We therefore sought to engineer alternative immune cell types to inhibit melanoma progression. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells; however, whether these engineered macrophages can effectively inhibit melanoma growth is unknown. To determine whether CAR-macrophages (CAR-Ms) specifically target and kill melanoma cells, we engineered CAR-Ms targeting chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. We developed 3D approaches to show that CSPG4-targeting CAR-Ms efficiently infiltrated melanoma spheroids. Furthermore, combining CSPG4-targeting CAR-Ms with strategies inhibiting CD47/SIRPα \"don't eat me\" signaling synergistically enhanced CAR-M-mediated phagocytosis and robustly inhibited melanoma spheroid growth in 3D. Importantly, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest engineering macrophages against melanoma antigens is a promising solid tumor immunotherapy approach for treating melanoma.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624701","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}
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