Cancer lettersPub Date : 2025-02-20DOI: 10.1016/j.canlet.2025.217572
Tianzhen Wang , Mingjiao Weng , Kai Li , Guoli Li , Shijie Hu , Ziyi Hu , Yanping Li , Muhan Li , Di Wu , Zhigang Liang , Fei Yu , Guangyu Wang , Xiaobo Li
{"title":"LIN28B enhances the chemosensitivity of colon cancer cells via inducing genomic instability by upsetting the balance between the production and removal of reactive oxygen species","authors":"Tianzhen Wang , Mingjiao Weng , Kai Li , Guoli Li , Shijie Hu , Ziyi Hu , Yanping Li , Muhan Li , Di Wu , Zhigang Liang , Fei Yu , Guangyu Wang , Xiaobo Li","doi":"10.1016/j.canlet.2025.217572","DOIUrl":"10.1016/j.canlet.2025.217572","url":null,"abstract":"<div><div>Genomic instability is an enabling characteristic that allows cancer cells to acquire additional hallmarks of cancer through the accumulation of alterations in driver genes. Furthermore, it creates opportunities to enhance the sensitivity of cancer cells to chemotherapeutic agents targeting DNA, owing to the presence of incomplete DNA damage repair pathways. This study identifies LIN28B as a crucial regulator of colon cancer cells' sensitivity to DNA damage- or repair-related compounds by promoting genomic instability. LIN28B mechanistically reduces glutathione (GSH) synthesis and activity by inhibiting the expression of four GSH metabolic enzymes (GCLC, G6PD, GSTM4, and GSTT2B), thereby reducing the capacity of cells to eliminate reactive oxygen species (ROS). LIN28B enhances the proinflammatory signaling pathway in cancer cells through the upregulation of ARID3A, a transcription factor that transactivates PTGES and PTGES2, resulting in increased production of PGE2, a key inflammatory mediator that can elevate ROS generation. In conclusion, LIN28B altered the equilibrium of ROS production and elimination in colon cancer, resulting in elevated ROS levels and subsequent genomic instability.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217572"},"PeriodicalIF":9.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476323","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}
Cancer lettersPub Date : 2025-02-20DOI: 10.1016/j.canlet.2025.217571
Ilona Skrabalak , Alicja Rajtak , Beata Malachowska , Natalia Skrzypczak , Karin A. Skalina , Chandan Guha , Jan Kotarski , Karolina Okla
{"title":"Therapy resistance: Modulating evolutionarily conserved heat shock protein machinery in cancer","authors":"Ilona Skrabalak , Alicja Rajtak , Beata Malachowska , Natalia Skrzypczak , Karin A. Skalina , Chandan Guha , Jan Kotarski , Karolina Okla","doi":"10.1016/j.canlet.2025.217571","DOIUrl":"10.1016/j.canlet.2025.217571","url":null,"abstract":"<div><div>Therapy resistance is a major barrier to achieving a cure in cancer patients, often resulting in relapses and mortality. Heat shock proteins (HSPs) are a group of evolutionarily conserved proteins that play a prominent role in the progression of cancer and drug resistance. HSP synthesis is upregulated in cancer cells, facilitating adaptation to various tumor microenvironment (TME) stressors, including nutrient deprivation, exposure to DNA‐damaging agents, hypoxia, and immune responses. In this review, we present background information about HSP-mediated cancer therapy resistance. Within this context, we emphasize recent progress in the understanding of HSP machinery, exploring the therapeutic potential of HSPs in cancer treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217571"},"PeriodicalIF":9.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476406","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}
Cancer lettersPub Date : 2025-02-20DOI: 10.1016/j.canlet.2025.217563
Min-Wei Yang , Qin-Yuan Jia , Da-Peng Xu , Yan-Nan Xu , Yan-Miao Huo , De-Jun Liu , Jian-Yu Yang , Xue-Liang Fu , Ding Ma , Zong-Hao Duan , Yi-Fan Yin , Xue-Shi-Yu Ma , Kan Xu , Rong Hua , Jun-Feng Zhang , Yong-Wei Sun , Wei Liu
{"title":"SRSF12 deficiency enhances tumor innervation and accelerates pancreatic tumorigenesis","authors":"Min-Wei Yang , Qin-Yuan Jia , Da-Peng Xu , Yan-Nan Xu , Yan-Miao Huo , De-Jun Liu , Jian-Yu Yang , Xue-Liang Fu , Ding Ma , Zong-Hao Duan , Yi-Fan Yin , Xue-Shi-Yu Ma , Kan Xu , Rong Hua , Jun-Feng Zhang , Yong-Wei Sun , Wei Liu","doi":"10.1016/j.canlet.2025.217563","DOIUrl":"10.1016/j.canlet.2025.217563","url":null,"abstract":"<div><div>The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor <em>SRSF12</em> as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed <em>Kras</em> mutation and <em>Srsf12</em> knockout mice (<em>Kras</em><sup>G12D</sup> <em>Srsf12</em> <sup>fl/fl</sup>) together with <em>Srsf12</em> <sup>fl/fl</sup> <em>Pdx1</em><sup>cre</sup> mice and found that depletion of <em>Srsf12</em> accelerated <em>Kras</em>-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217563"},"PeriodicalIF":9.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476329","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}
Cancer lettersPub Date : 2025-02-19DOI: 10.1016/j.canlet.2025.217574
Zihang Zeng , Zongbi Yi , Binghe Xu
{"title":"The biological and technical challenges facing utilizing circulating tumor DNA in non-metastatic breast cancer patients","authors":"Zihang Zeng , Zongbi Yi , Binghe Xu","doi":"10.1016/j.canlet.2025.217574","DOIUrl":"10.1016/j.canlet.2025.217574","url":null,"abstract":"<div><div>Breast cancer is one of the most prevalent cancers and has emerged as a major global challenge. Circulating tumor DNA (ctDNA), a liquid biopsy method, overcomes the accessibility limitations of tissue-based testing and is widely used for monitoring minimal residual disease and molecular relapse, predicting prognosis, evaluating the response of neoadjuvant therapy, and optimizing treatment decisions in non-metastatic breast cancer. However, the application of ctDNA still faces many challenges. Here, we survey the clinical applications of ctDNA in non-metastatic breast cancer and discuss the significant biological and technical challenges of utilizing ctDNA. Importantly, we investigate potential avenues for addressing the challenges. In addition, emerging technologies, including fragmentomics detection, methylation sequencing, and long-read sequencing, have clinical potential and could be a future direction. Proper utilization of machine learning facilitates the identification of meaningful patterns from complex fragment and methylation profiles of ctDNA. There is still a lack of clinical trials focused on the subsets of ctDNA (e.g., circulating mitochondrial DNA), ctDNA-inferred drug-resistant clonal evolution, tumor heterogeneity, and ctDNA-guided clinical decision-making in non-metastatic breast cancer. Due to regional differences in the number of registered clinical trials, it is essential to enhance communication and foster global collaboration to advance the field.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217574"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455014","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}
Cancer lettersPub Date : 2025-02-19DOI: 10.1016/j.canlet.2025.217569
Xiang Wang , Ruihao Huang , Lei Liu , Xiaoqi Wang , Xi Zhang
{"title":"Evaluation and preservation of fertility in patients with hematologic malignancies","authors":"Xiang Wang , Ruihao Huang , Lei Liu , Xiaoqi Wang , Xi Zhang","doi":"10.1016/j.canlet.2025.217569","DOIUrl":"10.1016/j.canlet.2025.217569","url":null,"abstract":"<div><div>For patients with hematologic malignancies, novel therapeutic strategies offer the potential to achieve a complete clinical response and long-term survival. However, declining fertility has become a significant concern, impacting long-term quality of life. Conventional high-dose chemotherapy and radiotherapy are known to reduce fertility or cause sterility. Moreover, limited clinical data are available on the effects of newer therapies, such as targeted treatments and chimeric antigen receptor (CAR)-T cell therapy, on fertility. Additionally, there is no standard method for preserving fertility in these patients. Male patients can opt for sperm cryopreservation, whereas female patients may preserve fertility through embryo, oocyte, or ovarian tissue cryopreservation. However, preserving fertility in prepubescent patients remains particularly challenging. Therefore, hematologists must educate patients about the potential gonadal toxicity of cancer treatments and offer the most appropriate fertility preservation options.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217569"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472439","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}
Cancer lettersPub Date : 2025-02-19DOI: 10.1016/j.canlet.2025.217573
Ya-Xian Zhong , Huan-Bin Zhao , Meng-Han Lian , Jia-Ming Shen , Cheng-Xiao Li , Hong-Ming Ma , Dan Xu , Guo-Qiang Chen , Cheng Zhang
{"title":"SUMOylated hnRNPM suppresses PFKFB3 phosphorylation to regulate glycolysis and tumorigenesis","authors":"Ya-Xian Zhong , Huan-Bin Zhao , Meng-Han Lian , Jia-Ming Shen , Cheng-Xiao Li , Hong-Ming Ma , Dan Xu , Guo-Qiang Chen , Cheng Zhang","doi":"10.1016/j.canlet.2025.217573","DOIUrl":"10.1016/j.canlet.2025.217573","url":null,"abstract":"<div><div>Heterogeneous nuclear ribonucleoprotein M (hnRNPM), a splicing regulatory factor with a majority of studies focused on its RNA-binding properties and effects on splicing outcome, is implicated in the progression of various kinds of human cancers, but its mechanisms remain largely enigmatic. Applying the global SUMOylated proteomic screening in colorectal cancer cells, herein we find that hnRNPM is SUMOylated at lysine 17 and Sentrin-specific protease 1 (SENP1) is essential for its de-SUMOylation. Although hnRNPM SUMOylation does not affect its known pre-mRNA splicing-related effects, more intriguingly, it remarkably influences lactate production. Mechanistically, SUMOylated hnRNPM interacts with 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to affect its localization and inhibit its phosphorylation, thus suppressing glycolysis. Accordingly, SUMO-deficient hnRNPM promotes colorectal cancer cell proliferation and tumorigenesis in mice. Also, a negative correlation between hnRNPM SUMOylation and SENP1 expression or phosphorylated PFKFB3 levels can be found in CRC patient samples. These findings not only enhance our understanding of the multifaceted roles of hnRNPM in cancer biology but also open new avenues for the development of targeted therapies aimed at modulating hnRNPM SUMOylation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217573"},"PeriodicalIF":9.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472443","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}
Cancer lettersPub Date : 2025-02-18DOI: 10.1016/j.canlet.2025.217568
Hei Yeung Chan , Qi Wang , Andrew Howie , Joseph Bucci , Peter Graham , Yong Li
{"title":"Extracellular vesicle biomarkers redefine prostate cancer radiotherapy","authors":"Hei Yeung Chan , Qi Wang , Andrew Howie , Joseph Bucci , Peter Graham , Yong Li","doi":"10.1016/j.canlet.2025.217568","DOIUrl":"10.1016/j.canlet.2025.217568","url":null,"abstract":"<div><div>Radiotherapy (RT) remains a cornerstone in the treatment of prostate cancer (PCa). Extracellular vesicles (EVs), nano-sized particles secreted by cells, play important roles in intercellular communication within the tumour microenvironment (TME) and contribute to tumour growth, metastasis, and therapy resistance. Recent advancements demonstrate the potential of EVs as biomarkers for cancer diagnosis, prognosis, and treatment monitoring. Accumulating evidence supports the role of EVs in modulating RT outcomes by shaping the TME, mediating radioresistance, and influencing cancer metastasis. Despite substantial progress, challenges remain, including the heterogeneity of EV biogenesis, variability in cargo composition, and the absence of standardised methods for EV isolation and characterisation. While the therapeutic and diagnostic prospects of EVs in PCa management are promising, further research is needed to clarify the mechanisms through which EVs impact RT and to translate these findings into clinical practice. Incorporating EV research into PCa treatment paradigms could enhance diagnostic accuracy, enable real-time monitoring of RT responses, and support the development of new targeted therapeutic strategies. This review discusses recent progress in understanding EVs in the context of RT for PCa, focuses on their roles in modulating tumour growth, contributing to radioresistance within the TME, and facilitating the monitoring of RT efficacy and recurrence. In addition, the potential of EVs as biomarkers for liquid biopsy and their applications in enhancing radiosensitivity or overcoming radioresistance is also explored.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217568"},"PeriodicalIF":9.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455012","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}
Cancer lettersPub Date : 2025-02-18DOI: 10.1016/j.canlet.2025.217567
Lu Li , Jinyun Dong , Chunwei Xu , Shiqun Wang
{"title":"Lactate drives senescence-resistant lineages in hepatocellular carcinoma via histone H2B lactylation of NDRG1","authors":"Lu Li , Jinyun Dong , Chunwei Xu , Shiqun Wang","doi":"10.1016/j.canlet.2025.217567","DOIUrl":"10.1016/j.canlet.2025.217567","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) treatment options remain limited despite advances in targeted therapies for molecularly-defined cancers. To address tumor heterogeneity, we reconstructed HCC clonal evolution through single-cell RNA sequencing trajectory analysis, identifying 902 signature genes across seven cellular states. Weighted gene co-expression network analysis of public HCC datasets revealed tumor-grade-associated modules and established a 14-gene prognostic model linked to clonal evolution. Central to this model is the LDHA-NDRG1 axis - two hypoxia-responsive regulators showing coordinated spatiotemporal expression patterns during cancer progression. Dual-expressing cell lineages correlated with poor prognosis and senescence resistance through LDHA-mediated lactylation of histone H2B at K58 on NDRG1, an epigenetic mechanism connecting metabolic reprogramming to senescence evasion. Therapeutically, dual inhibition of this axis extended survival in metastatic HCC murine models. Our findings reveal that lactate-driven epigenetic modification via the LDHA-NDRG1 axis creates a molecularly distinct subpopulation enabling senescence resistance, providing mechanistic insights into HCC heterogeneity. This work proposes a precision medicine strategy targeting lactylation-mediated epigenetic regulation, with implications for developing combination therapies and patient stratification based on clonal evolution patterns.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217567"},"PeriodicalIF":9.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455013","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":"mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer","authors":"Tomohiro Tamura , Shimpei Nagai , Kenta Masuda , Keiyo Imaeda , Eiji Sugihara , Juntaro Yamasaki , Miho Kawaida , Yuji Otsuki , Kentaro Suina , Hiroyuki Nobusue , Tomoko Akahane , Tatsuyuki Chiyoda , Iori Kisu , Yusuke Kobayashi , Kouji Banno , Kazuhiro Sakurada , Hajime Okita , Rui Yamaguchi , Ahmed Ashour Ahmed , Wataru Yamagami , Osamu Nagano","doi":"10.1016/j.canlet.2025.217565","DOIUrl":"10.1016/j.canlet.2025.217565","url":null,"abstract":"<div><div>Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in <em>BRCA1/2</em> wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"616 ","pages":"Article 217565"},"PeriodicalIF":9.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457009","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}
Cancer lettersPub Date : 2025-02-16DOI: 10.1016/j.canlet.2025.217566
Xiang Xu , Zhixin Huang , Hui Han , Zihan Yu , Linying Ye , Zeyu Zhao , Yan Qian , Ying Li , Risheng Zhao , Tianhao Zhang , Yinan Liu , Junchao Cai , Shuibin Lin , Ertao Zhai , Jianhui Chen , Shirong Cai
{"title":"N7-methylguanosine tRNA modification promotes gastric cancer progression by activating SDHAF4-dependent mitochondrial oxidative phosphorylation","authors":"Xiang Xu , Zhixin Huang , Hui Han , Zihan Yu , Linying Ye , Zeyu Zhao , Yan Qian , Ying Li , Risheng Zhao , Tianhao Zhang , Yinan Liu , Junchao Cai , Shuibin Lin , Ertao Zhai , Jianhui Chen , Shirong Cai","doi":"10.1016/j.canlet.2025.217566","DOIUrl":"10.1016/j.canlet.2025.217566","url":null,"abstract":"<div><div>N<sup>7</sup>-methylguanosine (m<sup>7</sup>G) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of m<sup>7</sup>G tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated m<sup>7</sup>G tRNA modifications in promoting GC progression. Upregulation of m<sup>7</sup>G methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression <em>in vitro</em> and <em>in vivo</em>. Mechanistically, METTL1 knockdown reduces the expression of m<sup>7</sup>G-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated m<sup>7</sup>G tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"615 ","pages":"Article 217566"},"PeriodicalIF":9.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436974","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}