Liquid–liquid phase separation in tumor biology

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июль 8, 2022

Abstract Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response repair, transcription, signal transduction. Dysregulation these cellular processes key event initiation and/or evolution cancer, emerging evidence has linked formation to malignant transformations tumor biology. In this review, we comprehensively summarize detailed mechanisms condensate biophysical function review recent major advances toward elucidating multiple involved cancer cell pathology driven by aberrant LLPS. addition, discuss therapeutic perspectives research most developed drug candidates targeting modulation that can be used combat tumorigenesis.

Язык: Английский

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Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem

Theranostics, Год журнала: 2023, Номер 13(5), С. 1607 - 1631

Опубликована: Янв. 1, 2023

Nasopharyngeal carcinoma (NPC) is a particular entity of head neck cancer that generally regarded as genetic disease with diverse intertumor and intratumor heterogeneity. This perspective review mainly outlines the up-to-date knowledge ecology NPC progression, presents number conceptual stepping-stones. At beginning, I explicitly advocate nature (cancer) not but an ecological disease: multidimensional spatiotemporal "unity evolution" pathological ecosystem. The hallmarks proposed to act factors population fitness. Subsequently, cells are described invasive species its metastasis multidirectional dispersal. foundational principles include intraspecific relationship (e.g. communication) interspecific competition, predation, parasitism mutualism) interpreted understand progression. "Mulberry-fish-ponds" model can well illustrate dynamic reciprocity Tumor-host interface transition zone cancer, tumor buddings should be recognized islands separated from mainland. It noted tumor-host has significantly molecular functional edge effect because curvature irregularity. Selection driving therapy including hyperthermia for patients, future perspectives in such field "ecological pathology", "multidimensional tumoriecology" also discussed. advance "nothing evolution or makes sense except light other". tree constructed comprehensively point out research direction. Taken together, establishment theory might provide novel framework paradigm our understanding complex causal process potential preventive therapeutic applications patients.

Язык: Английский

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Disrupting the phase separation of KAT8–IRF1 diminishes PD-L1 expression and promotes antitumor immunity

Nature Cancer, Год журнала: 2023, Номер 4(3), С. 382 - 400

Опубликована: Март 9, 2023

Abstract Immunotherapies targeting the PD-1/PD-L1 axis have become first-line treatments in multiple cancers. However, only a limited subset of individuals achieves durable benefits because elusive mechanisms regulating PD-1/PD-L1. Here, we report that cells exposed to interferon-γ (IFNγ), KAT8 undergoes phase separation with induced IRF1 and forms biomolecular condensates upregulate PD-L1. Multivalency from both specific promiscuous interactions between is required for condensate formation. KAT8–IRF1 condensation promotes K78 acetylation binding CD247 (PD-L1) promoter further enriches transcription apparatus promote PD-L1 mRNA. Based on mechanism formation, identified 2142–R8 blocking peptide, which disrupts formation consequently inhibits expression enhances antitumor immunity vitro vivo. Our findings reveal key role regulation provide competitive peptide enhance immune responses.

Язык: Английский

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Cytoskeleton remodeling mediated by circRNA-YBX1 phase separation suppresses the metastasis of liver cancer

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(30)

Опубликована: Июль 17, 2023

Metastasis, especially intrahepatic, is a major challenge for hepatocellular carcinoma (HCC) treatment. Cytoskeleton remodeling has been identified as vital process mediating intrahepatic spreading. Previously, we reported that HCC tumor adhesion and invasion were modulated by circular RNA (circRNA), which emerged an important regulator of various cellular processes implicated in cancer progression. Here, uncovered nuclear circRNA, circASH2, preferentially lost tissues inhibits metastasis altering cytoskeleton structure. Tropomyosin 4 (TPM4), critical binding protein actin, turned out to be the target circASH2 was posttranscriptionally suppressed. Such regulation based on messenger (mRNA)/precursormRNA splicing degradation process. Furthermore, liquid–liquid phase separation Y-box 1 (YBX1) enhanced augments TPM4 transcripts decay. Together, our data have revealed tumor-suppressive circRNA and, more importantly, fine mechanism

Язык: Английский

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Small-molecule properties define partitioning into biomolecular condensates

Nature Chemistry, Год журнала: 2024, Номер 16(11), С. 1794 - 1802

Опубликована: Сен. 13, 2024

Язык: Английский

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Micronuclei and Cancer

Cancer Discovery, Год журнала: 2024, Номер 14(2), С. 214 - 226

Опубликована: Янв. 10, 2024

Chromosome-containing micronuclei are a feature of human cancer. Micronuclei arise from chromosome mis-segregation and characterize tumors with elevated rates chromosomal instability. Although their association cancer has been long recognized, only recently have we broadened our understanding the mechanisms that govern formation role in tumor progression. In this review, provide brief historical account micronuclei, depict underpinning creation, illuminate capacity to propel evolution through genetic, epigenetic, transcriptional transformations. We also posit prospect leveraging as biomarkers therapeutic targets chromosomally unstable cancers. cells serve pivotal catalysts for progression, instigating transformative genomic, alterations. This comprehensive review not synthesizes present comprehension but outlines framework translating knowledge into pioneering therapeutics, thereby illuminating novel paths personalized management.

Язык: Английский

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Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Chemical Society Reviews, Год журнала: 2024, Номер 53(10), С. 4976 - 5013

Опубликована: Янв. 1, 2024

Protein misfolding and amyloid aggregation, linked to neurodegenerative diseases, can result from liquid–liquid phase separation (LLPS) a subsequent liquid-to-solid transition. This represents LLPS as generic mechanism in nucleation.

Язык: Английский

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G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 5, 2024

Abstract G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel motility MAZ phase-separated condensates and subsequently transcription. Zinc finger (ZF) 2 of is a responsible for G4 binding, while ZF3-5, not highly disordered region, critical condensation. nuclear puncta overlaps with signals various coactivators including BRD4, MED1, CDK9 active RNA polymerase II, as well activation histone markers. mutants lacking either binding or phase separation ability did form puncta, showed deficiencies promoting hepatocellular carcinoma cell proliferation xenograft tumor formation. Overall, unveiled facilitate compartmentalize expression exacerbate hepatocarcinogenesis.

Язык: Английский

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COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, enable more realistic modeling involving domains without additional costs. COCOMO2 was parametrized directly solubility data improve performance predicting concentration-dependent broader range biomolecular systems compared original version. enables new applications study condensates involve IDPs together assembly also provides expanded foundation development multiscale approaches span residue-level atomistic resolution.

Язык: Английский

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The phenylalanine-and-glycine repeats of NUP98 oncofusions form condensates that selectively partition transcriptional coactivators

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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