Oncogenesis最新文献

{"title":"CD147-high extracellular vesicles promote gastric cancer metastasis via VEGF/AKT/eNOS and AKT/mTOR pathways.","authors":"Chen-Li Zhang, Chan-Yuan Zhao, Jia-Ming Dong, Cun-Pu Du, Bin-Sheng Wang, Chen-Yu Wang, Wei Liu, Yu-Ping Wang, Xiao-Yu Zhang, Quan Zhou, Wei Cai, Yun Dang, Li-Na Shang, Ai-Jun Yang, Min Wang, Min Li","doi":"10.1038/s41389-025-00564-3","DOIUrl":"10.1038/s41389-025-00564-3","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) play a pivotal role in intercellular communication and are closely linked to cancer progression and metastasis. Our previous studies have shown that gastric cancer cell-derived EVs can promote tumor metastasis by increasing the permeability of the endothelial barrier. However, it remains unclear which effector molecule in the EV structure is the key factor of EV-mediated tumor metastasis and the underlying molecular mechanism. In this study, we found that CD147 is a key molecule highly expressed in gastric cancer-derived EVs and confirmed the role of CD147-high EVs from gastric cancer cells in promoting endothelial dysfunction and tumor metastasis. Our results showed that CD147-high EVs activated the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K signaling pathways, leading to endothelial cytoskeletal reorganization and internalization of VE-cadherin, which significantly compromised endothelial barrier integrity, increased vascular leakage, enhanced transendothelial migration of tumor cell, and promoted the formation of metastatic tumors. Furthermore, detection of CD147 levels in gastric cancer tissues and plasma EVs indicated that high CD147 expression was associated with advanced tumor stage, poor prognosis, and reduced survival. Our findings suggest that CD147-high EVs are critical mediators of tumor-endothelial interactions and potential diagnostic and prognostic biomarkers for gastric cancer. Their potential as therapeutic targets for gastric cancer is underscored. This figure illustrates the proposed mechanism by which CD147-high gcEVs promote tumor metastasis. CD147-high EVs are released from gastric cancer cells and interact with endothelial cells in the tumor microenvironment. Upon uptake by endothelial cells, CD147-high gcEVs activate the key signaling pathways, including the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K pathway, which collectively facilitate the metastatic potential of gastric cancer cells by promoting endothelial cell dysfunction and increasing vascular permeability.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ONC201 enhances the cytotoxic effect of cisplatin through ATF3/ATF4/CHOP in head and neck squamous cell carcinoma cells.","authors":"Hui-Ching Chuang, Ming-Hsien Tsai, Jiin-Haur Chuang, Ya-Ting Hong, Chih-Yen Chien, Ming-Huei Chou","doi":"10.1038/s41389-025-00563-4","DOIUrl":"10.1038/s41389-025-00563-4","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) remains a prevalent and challenging cancer to treat due to its genetic heterogeneity. Cisplatin resistance is one of important causes in treatment failure of locally advanced HNSCC. ONC201, a selective dopamine receptor D2 antagonist and mitochondrial ClpP agonist, has emerged as a potential antitumor agent in various malignancies. This study explores the therapeutic potential of ONC201, alone and in combination with cisplatin, in both cisplatin-sensitive and -resistant HNSCC cells, with an emphasis on endoplasmic reticulum (ER) stress-mediated apoptosis. A cisplatin-resistant HNSCC subline (OC2-CR1) was developed via long-term drug exposure. The treatment effectiveness of ONC201 alone and cisplatin in combination on cell viability, DNA damage, reactive oxygen species (ROS) production, and stress response markers were evaluated. ONC201 exhibited potent cytotoxicity in both cisplatin-sensitive and -resistant HNSCC cells, retaining efficacy in OC2-CR1 cells. Combined treatment with ONC201 and cisplatin demonstrated synergistic inhibition of proliferation and migration, with enhanced induction of apoptosis. Mechanistically, ONC201 induced ER stress-mediated cell death via ATF4/CHOP signaling in cisplatin-sensitive cells, while ATF3/CHOP predominated in resistant cells. In vivo, combination therapy significantly suppressed tumor growth in xenograft models, including cisplatin-resistant tumors, without inducing toxicity. Immunohistochemical analysis confirmed activation of CHOP in tumor tissues. Furthermore, clinical correlation revealed that low CHOP expression in OSCC patients was associated with increased recurrence risk and inferior recurrence-free survival significantly. This study provides compelling evidence that ONC201 enhances cisplatin efficacy through distinct, stress-mediated apoptotic pathways in HNSCC. The ability of ONC201 to overcome cisplatin resistance and its synergistic antitumor effects highlight its promise as a candidate for combination therapy. These findings support the translational potential of targeting the ATF3/ATF4/CHOP axis to improve outcomes in patients with cisplatin resistant HNSCC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NUCKS1 promotes invasion and metastasis of colorectal cancer by stabilizing HDAC2 and activating AKT.","authors":"Liaoliao Zhu, Ting Zhao, Haichuan Su, Junqiang Li, Xiangjing Shen, Liang Zhang, Jun Chen, Yang Song","doi":"10.1038/s41389-025-00562-5","DOIUrl":"10.1038/s41389-025-00562-5","url":null,"abstract":"<p><p>Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. Studies have found that NUCKS1 promotes tumor cell metastasis, yet its role in CRC invasion and metastasis remains unclear. Our findings revealed higher NUCKS1 expression in metastatic CRC compared to non-metastatic samples. Upregulation of NUCKS1 expression promoted the migration and invasion of CRC cells, while knockdown of NUCKS1 significantly inhibited the migration and invasion of CRC cells. Mechanistically, NUCKS1 was initially found to upregulate HDAC2 expression by inhibiting the lysosomal pathway, activating AKT, and thus promoting CRC invasion and metastasis. Moreover, HDAC2 inhibitor Santacruzamate A or AKT inhibitor LY294002 rescued the migration and invasion of CRC cells caused by NUCKS1 overexpression. In vivo, by injecting CRC cells into the tail vein of a nude mouse model, we found that overexpression of NUCKS1-induced lung and liver metastasis was suppressed by HDAC2 knockdown or intraperitoneal administration of the HDAC2 inhibitor Santacruzamate A. Meanwhile, AKT inhibitor LY294002 significantly inhibited lung and liver metastasis caused by overexpression of HDAC2. The expression levels of NUCKS1, HDAC2, and phosphorylated AKT were significantly positively correlated in human CRC tissues. These findings suggest that NUCKS1 contributes to CRC invasion and metastasis by stabilizing HDAC2 and activating AKT, highlighting NUCKS1 and HDAC2 as potential therapeutic targets for CRC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"19"},"PeriodicalIF":5.9,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma.","authors":"Shunpei Satoh, Mariko Hasegawa, Ryu Okada, Masayuki Haruta, Hisanori Takenobu, Miki Ohira, Takehiko Kamijo","doi":"10.1038/s41389-025-00561-6","DOIUrl":"10.1038/s41389-025-00561-6","url":null,"abstract":"<p><p>Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex 1 (PRC)-mediated H2AK119 monoubiquitination (H2AK119ub1) with subsequent silencing of tumor suppressor genes. Despite previous efforts, the biological and clinical significance of PRC1 remains unclear in neuroblastoma (NB), an aggressive sympathoadrenal solid tumor in children. In this study, we demonstrated that knockdown of RING1A, one of the E3 ubiquitin ligases of PRC1, reduced cell viability and enrichment of H2AK119ub1 in NB cells. Transcriptional profiling revealed RING1A-specific targets, whose lower expression was associated with poor outcomes in NB patients. Among these genes, BTG2, a component of the CCR4-NOT polyA deadenylase complex, harbored a hypomethylated CpG island occupied by H2AK119ub1 and accessory proteins of noncanonical PRC1.1 (ncPRC1.1). Biological experiments uncovered that BTG2 suppressed NB cell growth in vitro and inhibited tumor formation in vivo. Moreover, BTG2 perturbed cell cycle progression and selectively destabilized the mRNAs of the cyclin genes CCNA2, CCNB1, and CCNB2. In NB patient cohorts, lower expression of BTG2 was associated with poor outcomes and inversely correlated with those cyclin gene expression. Collectively, we have uncovered a crosstalk between epigenetic modifications and post-transcriptional regulations, in which ncPRC1.1-mediated silencing of BTG2 retains cyclin gene expression and cell proliferation in NB. This study provides new insights into how epigenetic pathways contribute to NB malignancy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"18"},"PeriodicalIF":5.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β signaling redirects Sox11 gene regulatory activity to promote partial EMT and collective invasion of oncogenically transformed intestinal organoids.","authors":"Yu-Hsiang Teng, Bismark Appiah, Geoffroy Andrieux, Monika Schrempp, Katja Rose, Angelika Susanna Hofmann, Manching Ku, Sven Beyes, Melanie Boerries, Andreas Hecht","doi":"10.1038/s41389-025-00560-7","DOIUrl":"10.1038/s41389-025-00560-7","url":null,"abstract":"<p><p>Cancer cells infiltrating surrounding tissue frequently undergo partial epithelial-mesenchymal transitions (pEMT) and employ a collective mode of invasion. How these phenotypic traits are regulated and interconnected remains underexplored. Here, we used intestinal organoids with colorectal cancer (CRC) driver mutations as model system to investigate the mechanistic basis of TGF-β1-induced pEMT and collective invasion. By scRNA-seq we identified multiple cell subpopulations representing a broad pEMT spectrum, where the most advanced pEMT state correlated with the transcriptional profiles of leader cells in collective invasion and a poor prognosis mesenchymal subtype of human CRC. Bioinformatic analyses pinpointed Sox11 as a transcription factor gene whose expression peaked in the potential leader/pEMT^high cells. Immunofluorescence staining confirmed Sox11 expression in cells at the invasive front of TGF-β1-treated organoids. Loss-of-function and overexpression experiments showed that Sox11 is necessary, albeit not sufficient, for TGF-β1-induced pEMT and collective invasion. In human CRC samples, elevated SOX11 expression was associated with advanced tumor stages and worse prognosis. Unexpectedly, aside from orchestrating the organoid response to TGF-β1, Sox11 controlled expression of genes related to normal gut function and tumor suppression. Apparently, Sox11 is embedded in several distinct gene regulatory circuits, contributing to intestinal tissue homeostasis, tumor suppression, and TGF-β-mediated cancer cell invasion.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"17"},"PeriodicalIF":5.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SYT7 accelerates nasopharyngeal carcinoma progression via ALDH1A3-mediated STAT3 signaling activation.","authors":"Kai Xu, Yifan Kang, Jing Wang, Ying Hou, Wenxiang Zheng, Wenxiu Tian, Chuanjie Liang, Yongliang Liu, Xinxin Xiang","doi":"10.1038/s41389-025-00558-1","DOIUrl":"https://doi.org/10.1038/s41389-025-00558-1","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) is a special histological and ethical type of head and neck cancer with unsatisfactory clinical outcome. Thus, exploring effective molecular targets is critical for NPC treatment. We observed increased expression levels of synaptotagmin-7 (SYT7) in NPC tissues, which correlated with unfavorable prognoses. Furthermore, knockdown of SYT7 in NPC cells suppressed proliferation and migration rates, and enhanced apoptosis. In contrast, overexpression of SYT7 accelerated NPC tumor growth. Using whole-genome gene arrays and immunoprecipitation-mass spectrometry assays, aldehyde dehydrogenase 1 family member A3 (ALDH1A3), a regulator of glycolytic metabolism, was identified as a critical downstream target of SYT7. Mechanistically, SYT7 binds and promotes ALDH1A3 deubiquitination, resulting in decreased ALDH1A3 degradation. Notably, we also observed an increased expression of ALDH1A3 in NPC. More importantly, the knockdown of ALDH1A3 resulted in suppressed proliferation, migration, glycolysis, and promoted apoptosis, all of which could be restored by the overexpression of SYT7 in NPC cells. Taken together, we found that SYT7 increases ALDH1A3-mediated STAT3 activation and glycolysis, contributing to NPC progression, which provides a possible molecular mechanism for the development of targeted therapeutics interventions.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"16"},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLEKHA4 is transcriptionally regulated by HOXD9 and regulates glycolytic reprogramming and progression in glioblastoma via activation of the STAT3/SOCS-1 pathway.","authors":"Dainan Zhang, Xiaoyin Wang, Meng Xiao, Shunchang Ma, Shaomin Li, Wang Jia","doi":"10.1038/s41389-025-00559-0","DOIUrl":"https://doi.org/10.1038/s41389-025-00559-0","url":null,"abstract":"<p><p>Recent studies have demonstrated that PLEKHA4 promotes tumor growth in some cancers, such as small-cell lung cancer, melanoma, and hepatic carcinomas; however, the underlying mechanism in glioblastoma remains ambiguous. Bioinformatic was used to analysis PLEKHA4 expression. In vitro and in vivo experiments were conducted to detect the effect of PLEKHA4 on glioblastoma cell glycolytic reprogramming and progression. GSEA was used to analyze the signal pathways related to PLEKHA4. Pharmacological methods further validated the role of activation pathways. We evaluated the effects of PLEKHA4 knockdown combined with temozolomide (TMZ) on glioblastoma cell proliferation and apoptosis in vitro and in vivo. We observed an overexpression of PLEKHA4 in GBM cell lines, resulting in enhanced cell proliferation, inhibited apoptosis, and promoted glycolysis. Mechanistically, our study demonstrated that PLEKHA4 mediates cell proliferation, apoptosis, and glycolysis via the STAT3/SOCS1 signaling pathway. Additionally, HOXD9 was predicted using Jasper, which is a transcription factor that binds to the PLEKHA4 promoter region. Knocking down PLEKHA4 combined with TMZ inhibited cell proliferation and promoted cell apoptosis in vitro and in vivo. Our results indicated that HOXD9-medicated PLEKHA4 regulates glioblastoma cell proliferation and glycolysis via activation of the STAT3/SOCS1 pathway.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"15"},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2/MDMX and inactivation of p53.","authors":"Djazia Haferssas, Marion Dubuissez, Jonatan Barrera-Chimal, Clémence Messmer, El Bachir Affar, Bruno Larrivée, Xue-Song Liu, Casimiro Gerarduzzi","doi":"10.1038/s41389-025-00552-7","DOIUrl":"https://doi.org/10.1038/s41389-025-00552-7","url":null,"abstract":"<p><p>Aberrant Receptor Tyrosine Kinase (RTK) signaling allows cancer cells to modulate survival, proliferation, and death, leading to tumorigenesis and chemoresistance. In leukemia, the RTK FMS-Related Tyrosine Kinase 4 (FLT4) (also known as VEGFR3, Vascular Endothelial Growth Factor Receptor- 3) is deregulated and correlates with cancer progression. However, the underlying consequences of its deregulation remain to be determined. Moreover, chemotherapy treatment requires that cancer cells retain a wild-type p53 to respond to DNA damage by tumor-suppressing activities, i.e. apoptosis. p53 activity is predominantly limited by its two major negative regulators, MDM2 and MDMX, which inactivate p53 by promoting its degradation and/or cytoplasmic localization. In this study, we have shown that activation of FLT4 by either overexpression or binding of its ligand, VEGFC, increases MDM2/MDMX stability, inactivates p53, and leads to resistance to DNA-damaging therapies. Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib. More importantly, leukemic cells treated with Palbociclib were more susceptible to DNA-damaging induction of apoptosis and had reduced cell proliferation. Leukemic cells overexpressing FLT4 displayed accelerated proliferation when injected into NOD-SCID mice as compared to wild-type cells. Altogether, our research proposes an innovative way to reactivate p53 in leukemia through the pharmacological inhibition of FLT4 signaling, which could serve as a potential treatment option. Schematic representation of FLT4-mediated MDM2/MDMX complex stabilization and suppression of p53 activity. VEGFC triggers FLT4 activation, leading to CDK4/6 activation, which phosphorylates MDMX on Ser-314. As a result, MDMX levels increase and bind to MDM2, stabilizing the MDM2/MDMX complex. This complex binds to p53, facilitating its suppression by reducing its transcriptional activity or enhancing its export to the cytoplasm for proteasomal degradation. Consequently, p53 inactivation promotes their survival, proliferation, and resistance to chemotherapy-induced apoptosis. The figure was created in BioRender.com.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"14"},"PeriodicalIF":5.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYCN and KAT2A form a feedforward loop to drive an oncogenic transcriptional program in neuroblastoma.","authors":"Zhihui Liu, Jason J Hong, Xiyuan Zhang, Carly M Sayers, Wendy Fang, Man Xu, Sydney Loria, Sakereh Maskal, Haiyan Lei, Haitao Wu, Rolf Swenson, Jordan L Meier, Jack F Shern, Carol J Thiele","doi":"10.1038/s41389-025-00557-2","DOIUrl":"https://doi.org/10.1038/s41389-025-00557-2","url":null,"abstract":"<p><p>The oncoprotein MYCN drives malignancy in various cancer types, including neuroblastoma (NB). However, our understanding of the mechanisms underlying its transcriptional activity and oncogenic function, as well as effective strategies to target it, remains limited. We discovered that MYCN interacts with the transcriptional coactivator KAT2A, and this interaction significantly contributes to MYCN's activity in NB. Our genome-wide analyses indicate MYCN recruits KAT2A to bind to DNA, thereby transcriptionally regulating genes associated with ribosome biogenesis and RNA processing. Moreover, we identified that MYCN directly activates KAT2A transcription, while KAT2A acetylates MYCN, increasing MYCN protein stability. Consequently, MYCN and KAT2A establish a feedforward loop that effectively regulates global gene expression, governing the malignant NB phenotype. Treatment of NB cells with a KAT2A Proteolysis Targeting Chimera (PROTAC) degrader reduces MYCN protein levels, antagonizes MYCN-mediated gene transcription regulation and suppresses cell proliferation. This study highlights the potential of transcriptional cofactors as viable targets for developing anti-MYCN therapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"13"},"PeriodicalIF":5.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12022051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EPHA5 promotes cell proliferation and inhibits apoptosis in Follicular Thyroid Cancer via the STAT3 signaling pathway.","authors":"Guorong Wang, Gaoran Xu, Yanan Fan, Guangzhi Wang, Jingchao Xu, Ning Zhang, Junzhu Chen, Huanjie Chen, Zhoufan Li, Xianwang Cao, Yongfu Zhao","doi":"10.1038/s41389-025-00556-3","DOIUrl":"https://doi.org/10.1038/s41389-025-00556-3","url":null,"abstract":"<p><p>Follicular thyroid carcinoma (FTC) is a common endocrine malignancy characterized by a higher propensity for invasion and metastasis compared to papillary thyroid carcinoma (PTC). Ephrin type A receptor 5 (EPHA5) is a crucial receptor tyrosine kinase involved in orchestrating diverse physiological processes, including apoptosis and proliferation. However, the mechanism of EPHA5 in FTC remains unclear. This study identified significant overexpression of EPHA5 in FTC. In vitro experiments showed that increased expression of EPHA5 promotes proliferation and inhibits apoptosis in FTC. Furthermore, EPHA5 activates the STAT3 signaling pathway. To explore the interaction between EPHA5 and the STAT3 signaling pathway, we used SH-4-54 (a STAT3-specific inhibitor). Interestingly, the influence of EPHA5 on proliferation and apoptosis was reduced upon combination with SH-4-54. In summary, this study unveils the involvement of the EPHA5-STAT3 signaling pathway in FTC and implies that the function of EPHA5 in FTC may partly depend on the STAT3 signaling pathway.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"12"},"PeriodicalIF":5.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}