{"title":"ZNF768 loss amplifies p53 action and reduces lung tumorigenesis in mice.","authors":"Audrey Poirier, Timon Utecht, Romain Villot, Yves Gélinas, Mathilde Mouchiroud, Manal Kordahi, Alona Kolnohuz, Coline Pasteur, Joanny Roy, Marie-Josée Beaulieu, Michèle Orain, Nolwenn Samson, Marie-Renée Blanchet, Philippe Joubert, Mathieu Laplante","doi":"10.1038/s41388-025-03352-w","DOIUrl":"https://doi.org/10.1038/s41388-025-03352-w","url":null,"abstract":"<p><p>Cell proliferation is a fundamental process required for organismal development, growth, and maintenance. Failure to control this process leads to several diseases, including cancer. Zinc finger protein 768 (ZNF768) is an emerging transcription factor that plays key roles in driving proliferation. In addition to controlling a gene network supporting cell division, ZNF768 physically interacts and inhibits the activity of the tumor suppressor p53. Although the importance of ZNF768 in promoting cell proliferation has been well demonstrated in vitro, the physiological and pathological roles of ZNF768 in vivo are still unknown. Here, we report the generation and characterization of a ZNF768 null mouse model. ZNF768 null mice are viable but show a growth defect early in life. Mouse embryonic fibroblasts (MEFs) isolated from ZNF768 null embryos exhibit higher p53 levels, premature senescence, and higher sensitivity to genotoxic stress. In line with these findings, ZNF768 null mice showed increased radiosensitivity. This effect was associated not only with higher expression of a subset of p53 target genes, but also with alterations in genes regulating transmembrane receptor signaling, cell adhesion, and growth. Because ZNF768 levels are elevated in tumors, we tested the impact of ZNF768 loss on cancer development in mice. Here, we show that ZNF768 deletion was sufficient to repress lung tumor development in a KRAS<sup>G12D</sup>-induced cancer mouse model. Overall, our findings establish ZNF768 as an important protein controlling cell proliferation that could potentially be targeted to reduce tumorigenesis.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710942","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 : 2025-03-25DOI: 10.1038/s41388-025-03351-x
Xuejiao Zhao, Huiling Lai, Guannan Li, Yu Qin, Ruqi Chen, Marilyne Labrie, Jayne M Stommel, Gordon B Mills, Ding Ma, Qinglei Gao, Yong Fang
{"title":"Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer.","authors":"Xuejiao Zhao, Huiling Lai, Guannan Li, Yu Qin, Ruqi Chen, Marilyne Labrie, Jayne M Stommel, Gordon B Mills, Ding Ma, Qinglei Gao, Yong Fang","doi":"10.1038/s41388-025-03351-x","DOIUrl":"10.1038/s41388-025-03351-x","url":null,"abstract":"<p><p>Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role for Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer. Illustration of Rictor/mTORC2 in promoting tumor onset by regulating glutathione metabolism and mediating oncogenic signaling.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710941","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":"LRRK2 reduces the sensitivity to TKI and PD-1 blockade in ccRCC via activating LPCAT1.","authors":"Yulong Hong, Wei Li, Zhuo Xing, Minghao Lu, Tianyu Tang, Liang Zhu, Wei Xiong, Huan Zhang, Wentao Liu, Shangqing Ren","doi":"10.1038/s41388-025-03289-0","DOIUrl":"10.1038/s41388-025-03289-0","url":null,"abstract":"<p><p>Tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) combination therapy is emerging as a major therapeutic strategy for advanced clear cell renal cell carcinoma (ccRCC). To define the druggable targets for improvement of TKI and ICI combination therapy in ccRCC, we analyzed a commercial protein kinase inhibitor dataset and a public ccRCC dataset and identified LRRK2 as a potential candidate that can be targeted by a small molecule inhibitor. We demonstrated that LRRK2 was transcriptionally upregulated by HIF2A and enabled to drive proliferation of ccRCC cells in a manner independent of its kinase activity. LRRK2 inhibits the RBX1-mediated degradation of lipid metabolism modulator LPCAT1 to reducing the sensitivity to TKI and PD-1 blockade in ccRCC. Specifically, LRRK2/LPCAT1 upregulated IL-1β expression levels through AKT and also increased IL-1β shearing by activating inflammasome. To target the kinase-independent activity of LRRK2, we developed an LR-protac and showed that LR-protac decreased LRRK2 protein level and enhanced the antitumor effect of PD-1 blockade and TKI in ccRCC. These data indicate that LRRK2 is a viable target for improvement of the efficacy of PD-1 blockade and TKI in ccRCC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692639","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 : 2025-03-21DOI: 10.1038/s41388-025-03343-x
Mia Hofstad, Andrea Woods, Karla Parra, Zoi E Sychev, Alice Mazzagatti, Xiaofang Huo, Lan Yu, Collin Gilbreath, Wei-Min Chen, Anthony J Davis, Peter Ly, Justin M Drake, Ralf Kittler
{"title":"Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer.","authors":"Mia Hofstad, Andrea Woods, Karla Parra, Zoi E Sychev, Alice Mazzagatti, Xiaofang Huo, Lan Yu, Collin Gilbreath, Wei-Min Chen, Anthony J Davis, Peter Ly, Justin M Drake, Ralf Kittler","doi":"10.1038/s41388-025-03343-x","DOIUrl":"10.1038/s41388-025-03343-x","url":null,"abstract":"<p><p>In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo, and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677141","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 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}
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