{"title":"“Intrinsic disorder-protein modification-LLPS-tumor” regulatory axis: From regulatory mechanisms to precision medicine","authors":"Zekun Cheng , Zehao Cheng , Yikai Zhang , Shubing Zhang","doi":"10.1016/j.bbcan.2024.189242","DOIUrl":"10.1016/j.bbcan.2024.189242","url":null,"abstract":"<div><div>Liquid-Liquid Phase Separation (LLPS) is an important mechanism for the formation of functional droplets. Protein modification is an important pathway to regulate LLPS, in which series of modifying groups realize dynamic regulation by changing the charge and spatial resistance of the modified proteins. Meanwhile, uncontrolled protein modifications associated with LLPS dysregulation are highly correlated with tumorigenesis and development, suggesting the existence of a potential regulatory axis between the three. In this review, we pioneered “protein modification-LLPS-tumor” regulatory axis and summarized protein modifications that regulate LLPS in cancer cells (including phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, lactate, ADP-ribosylation, O-glycosylation, and acylation) and their associated modification mechanisms. Finally, we outline advances in precision medicine based on this regulatory axis. The aim of this review is to expand the understanding of protein modifications regulating LLPS under normal or abnormal cellular conditions and to provide possible ideas for precision therapy.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189242"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822980","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}
Laura Rinaldi , Emanuela Senatore , Stella Feliciello , Francesco Chiuso , Luigi Insabato , Antonio Feliciello
{"title":"Kidney cancer: From tumor biology to innovative therapeutics","authors":"Laura Rinaldi , Emanuela Senatore , Stella Feliciello , Francesco Chiuso , Luigi Insabato , Antonio Feliciello","doi":"10.1016/j.bbcan.2024.189240","DOIUrl":"10.1016/j.bbcan.2024.189240","url":null,"abstract":"<div><div>Renal cell carcinoma (RCC) constitutes the most frequent kidney cancer of the adult population and one of the most lethal malignant tumors worldwide. RCC often presents without early symptoms, leading to late diagnosis. Prognosis varies widely based on the stage of cancer at diagnosis. In the early-stage, localized RCC has a relatively good prognosis, while advanced or metastatic RCC has a poor outcome. Obesity, smoking, genetic mutations and family history are all considered risk factors for RCC, while inherited disorders, such as Tuberous Sclerosis and von Hippel-Lindau syndrome, are causally associated with RCC development. Genetic screening, deep sequencing analysis, quantitative proteomics and immunostaining analysis on RCC tissues, biological fluids and blood samples have been employed to identify novel biomarkers, predisposing factors and therapeutic targets for RCC with important clinical implications for patient treatment. Combined approaches of gene-targeting strategies coupled to a deep functional analysis of cancer cell biology, both in vitro and in appropriate animal models of RCC, significantly contributed to identify and characterize relevant pathogenic mechanisms underlying development and progression of RCC. These studies provided also important cues for the generation of novel target-specific therapeutics that selectively restore deranged cancer cell signalling and dysfunctional immune checkpoints, positively impacting on the survival rate of treated RCC patients. In this review, we will describe the recent discoveries concerning the most relevant pathogenic mechanisms of RCC and will highlight novel therapeutic strategies that interrupt oncogenic pathways and restore immune defences in RCC patients.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189240"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824900","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}
Chenye Jiang , Zhe Hong , Shiwei Liu , Zongyuan Hong , Bo Dai
{"title":"Roles of CDK12 mutations in PCa development and treatment","authors":"Chenye Jiang , Zhe Hong , Shiwei Liu , Zongyuan Hong , Bo Dai","doi":"10.1016/j.bbcan.2024.189247","DOIUrl":"10.1016/j.bbcan.2024.189247","url":null,"abstract":"<div><div>Prostate cancer (PCa) is one of the most common cancers in men, and cyclin-dependent kinase 12 (CDK12) is emerging as a novel star player in the PCa tumorigenesis and progression to castration-resistant prostate cancer (CRPC). In PCa, CDK12 alterations are mostly loss-of-function mutations featuring intronic polyadenylation (IPA), focal tandem duplications (FTDs), and R-loops formation and transcription-replication conflicts (TRCs). The occurrence of IPA can result in homologous recombination deficiency (HRD) and androgen receptor (AR) variation. FTDs induce neoantigens and increase the expression of the AR, MYC, and other hotspot- associated genes. R-loops lead to TRCs and influence various cellular processes, including gene expression and genome stability. Due to the poor prognosis of CDK12-mutant PCa patients and the mediocre response to classic standard therapies, HRD and increased neoantigen levels have provided clinicians with new insights into alternative systematic treatments for this novel PCa phenotype. In this review, we summarize the roles of CDK12 mutations in PCa and discuss their clinical value, suggesting that CDK12 potentially represents a target for further research and the development of clinical strategies for PCa.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189247"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840603","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":"Emerging role of EZH2 in solid tumor metastasis","authors":"Ayushi Verma , Muqtada Ali Khan , Saumya Ranjan Satrusal , Dipak Datta","doi":"10.1016/j.bbcan.2024.189253","DOIUrl":"10.1016/j.bbcan.2024.189253","url":null,"abstract":"<div><div>Cancer cells experience multiple reversible changes during their metastatic spread. Epigenetic reprogramming, being reversible, has emerged as a critical driver of cancer metastasis. Epigenetic modulator Enhancer of Zeste homolog 2 (EZH2) is an important candidate for such reprogramming events. Both EZH2 protein and its catalytic function (H3K27me3) have been shown to promote solid tumor metastasis, although EZH2 functional inhibition has limited impact on primary tumor growth in some cancers. The dichotomous gene regulatory roles of EZH2 and H3K27me3 are currently being investigated to understand how they collectively contribute to promote metastasis. Here, we examine the multifaceted role of EZH2 in modulating solid tumor metastasis and its therapeutic potential.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189253"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900627","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}
Yue Ji , Yingchi Lin , Jing He , Yuanyuan Xie , Wenmin An , Xinyu Luo , Xue Qiao , Zhenning Li
{"title":"Research progress of mitochondria and cytoskeleton crosstalk in tumour development","authors":"Yue Ji , Yingchi Lin , Jing He , Yuanyuan Xie , Wenmin An , Xinyu Luo , Xue Qiao , Zhenning Li","doi":"10.1016/j.bbcan.2024.189254","DOIUrl":"10.1016/j.bbcan.2024.189254","url":null,"abstract":"<div><div>During tumour progression, organelle function undergoes dramatic changes, and crosstalk among organelles plays a significant role. Crosstalk between mitochondria and other organelles such as the endoplasmic reticulum and cytoskeleton has focussed attention on the mechanisms of tumourigenesis. This review demonstrates an overview of the molecular structure of the mitochondrial-cytoskeletal junction and its biological interactions. It also presents a detailed and comprehensive description of mitochondrial-cytoskeletal crosstalk in tumour occurrence and development, including tumour cell proliferation, apoptosis, autophagy, metabolic rearrangement, and metastasis. Finally, the application of crosstalk in tumour therapy, including drug combinations and chemoresistance, is discussed. This review offers a theoretical basis for establishing mitochondrial-cytoskeletal junctions as therapeutic targets, and offers novel insights into the future management of malignant tumours.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189254"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900701","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":"Lipid metabolism in ferroptosis: Unraveling key mechanisms and therapeutic potential in cancer","authors":"Jaewang Lee , Jong-Lyel Roh","doi":"10.1016/j.bbcan.2024.189258","DOIUrl":"10.1016/j.bbcan.2024.189258","url":null,"abstract":"<div><div>Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has emerged as a critical area of research for cancer therapy. This review delves into the intricate relationship between lipid metabolism and ferroptosis, emphasizing the impact of lipidome remodeling on cancer cell susceptibility. We explore key mechanisms, such as the role of polyunsaturated fatty acids and phosphatidylethanolamines in ferroptosis induction, alongside the protective effects of monounsaturated fatty acids and their regulatory enzymes. We also discuss the influence of dietary fatty acids, lipid droplets, and the epithelial-to-mesenchymal transition on ferroptosis and cancer resistance. By integrating current findings on enzymatic regulation, lipid peroxidation pathways, and metabolic adaptations, this review highlights potential therapeutic strategies targeting lipid metabolism to enhance ferroptosis-based cancer treatments. Our goal is to provide a comprehensive overview that underscores the significance of lipid metabolic pathways in ferroptosis and their implications for developing novel cancer therapies.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189258"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924176","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":"Circulating tumor cells in solid malignancies: From advanced isolation technologies to biological understanding and clinical relevance in early diagnosis and prognosis","authors":"Divya Janjua, Apoorva Chaudhary, Udit Joshi, Tanya Tripathi, Alok Chandra Bharti","doi":"10.1016/j.bbcan.2024.189236","DOIUrl":"10.1016/j.bbcan.2024.189236","url":null,"abstract":"<div><div>Circulating tumor cells (CTCs) are shed from primary tumors and travel through the body via circulation, eventually settling to form micrometastases under favorable conditions. Numerous studies have identified CTCs as a negative prognostic indicator for survival across various cancer types. CTCs mirror the current heterogeneity and genetic and biological state of tumors, making their study invaluable for understanding tumor progression, cell senescence, and cancer dormancy. However, their isolation and characterization still poses a major challenge that limits their clinical translation. A wide array of methods, each with different levels of specificity, utility, cost, and sensitivity, have been developed to isolate and characterize CTCs. Moreover, innovative techniques are emerging to address the limitations of existing methods. In this review, we provide insights into CTC biology addressing spectra of markers employed for molecular analysis and functional characterization. It also emphasizes current label-dependent and label-independent isolation procedures, addressing their strengths and limitations.</div></div><div><h3>Significance</h3><div>A comprehensive overview of CTC biology, their molecular and functional characterization, along with their current clinical utility will help in understanding the present-day extent to which the clinical potential of CTCs is getting tapped in personalized medicine.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189236"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815253","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}
Eui-Jeong Han , Ji-Seon Ahn , Yu-Jin Choi , Da-Hye Kim , Jong-Soon Choi , Hea-Jong Chung
{"title":"Exploring the gut microbiome: A potential biomarker for cancer diagnosis, prognosis, and therapy","authors":"Eui-Jeong Han , Ji-Seon Ahn , Yu-Jin Choi , Da-Hye Kim , Jong-Soon Choi , Hea-Jong Chung","doi":"10.1016/j.bbcan.2024.189251","DOIUrl":"10.1016/j.bbcan.2024.189251","url":null,"abstract":"<div><div>The gut microbiome, a complex community of trillions of microorganisms in the intestines, is crucial in maintaining human health. Recent advancements in microbiome research have unveiled a compelling link between the gut microbiome and cancer development and progression. Alterations in the composition and function of the gut microbiome, known as dysbiosis, have been implicated in various types of cancer, including, esophageal, liver, colon, pancreatic, and gastrointestinal. However, the specific gut microbial strains associated with the development or progression of cancers in various tissues remain largely unclear. Here, we summarize current research findings on the gut microbiome of multiple cancers. This review aims to identify key gut microbial targets that closely influence cancer development based on current research findings. To accurately evaluate the effectiveness of the gut microbiome as a clinical tool for cancer, further research is needed to explore its potential as a biomarker and therapeutic strategy.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189251"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886602","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":"Mitochondrial DNA-activated cGAS-STING pathway in cancer: Mechanisms and therapeutic implications","authors":"Lintao Xia , Xiuli Yan , Hui Zhang","doi":"10.1016/j.bbcan.2024.189249","DOIUrl":"10.1016/j.bbcan.2024.189249","url":null,"abstract":"<div><div>Mitochondrial DNA (mtDNA), a circular double-stranded DNA located within mitochondria, plays a pivotal role in mitochondrial-induced innate immunity, particularly via the cyclic GMP-AMP synthase (cGAS)-STING pathway, which recognizes double-stranded DNA and is crucial for pathogen resistance. Recent studies elucidate the interplay among mtDNA, the cGAS-STING pathway, and neutrophil extracellular traps (NETs) in the context of cancer. mtDNA uptake by recipient cells activates the cGAS-STING pathway, while mtDNA leakage reciprocally regulates NET release, amplifying inflammation and promoting NETosis, a mechanism of tumor cell death. Autophagy modulates these processes by clearing damaged mitochondria and degrading cGAS, thus preventing mtDNA recognition. Tumor microenvironmental factors, such as metabolic reprogramming and lipid accumulation, induce mitochondrial stress, ROS production, and further mtDNA leakage. This review explores strategies in cancer drug development that leverage mtDNA leakage to activate the cGAS-STING pathway, potentially converting ‘cold tumors’ into ‘hot tumors,’ while discussing advancements in targeted therapies and proposing new research methodologies.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189249"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866304","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":"SENP3: Cancers and diseases","authors":"Lianglong Chen, Yaning Che, Chao Huang","doi":"10.1016/j.bbcan.2025.189260","DOIUrl":"10.1016/j.bbcan.2025.189260","url":null,"abstract":"<div><div>SUMOylation is a protein modification process that involves the covalent attachment of a small ubiquitin-like modifier (SUMO) to a specific lysine residue on the target protein. This modification can influence the function, localization, stability, and interactions of proteins, thereby regulating various cellular processes. Altering the SUMOylation of certain proteins is expected to be a potential approach for treating specific cancers and diseases. Among these, SENP3 can affect target proteins by regulating the deSUMOylation process, which in turn influences the transcriptional activity of downstream genes, playing a role in either promoting or inhibiting cancer. SENP3 regulates the SUMO status of proteins in numerous signaling pathways, modulating the activity of specific signaling molecules to impact cellular responses and tumor progression. Additionally, SENP3 promotes cell growth and division by deSUMOylating key cyclins. In the context of DNA repair, SENP3 regulates the activity of proteins associated with DNA repair by deSUMOylating repair factors, thereby enhancing DNA repair and maintaining genome stability. Furthermore, SENP3 has specific functions in various other diseases. The complex roles of SENP3 indicate its potential as both a therapeutic target and a biomarker.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 1","pages":"Article 189260"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967534","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}