Biomolecular Condensates and Cancer

Cancer Cell, Год журнала: 2021, Номер 39(2), С. 174 - 192

Опубликована: Янв. 9, 2021

Язык: Английский

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Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations

Cell, Год журнала: 2020, Номер 183(7), С. 1742 - 1756

Опубликована: Дек. 1, 2020

Язык: Английский

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DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy

Cancers, Год журнала: 2020, Номер 12(8), С. 2123 - 2123

Опубликована: Июль 31, 2020

DNA methyltransferases are an essential class of modifiers in epigenetics. In mammals, DNMT1, DNMT3A and DNMT3B participate methylation to regulate normal biological functions, such as embryo development, cell differentiation gene transcription. Aberrant functions DNMTs frequently associated with tumorigenesis. DNMT aberrations usually affect tumor-related factors, hypermethylated suppressor genes genomic instability, which increase the malignancy tumors, worsen prognosis for patients, greatly difficulty cancer therapy. However, impact on tumors is still controversial, therapeutic approaches targeting under exploration. Here, we summarize paradoxes discuss some emerging strategies may provide novel ideas

Язык: Английский

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Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Март 1, 2021

Cancer is a disease which frequently has poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments impedes the clinical outcomes. Besides active driven by genetic epigenetic alterations in tumor cells, microenvironment (TME) also reported be crucial regulator tumorigenesis, progression, resistance. Here, we propose that adaptive mechanisms of are closely connected with TME rather than depending on non-cell-autonomous changes response treatment. comprehensive understanding need further investigation fully elucidate resistance, many targeting successful. In this review, report recent advances concerning molecular events important factors involved TME, particularly focusing contributions provide insights into potential methods or translational medicine overcome therapy

Язык: Английский

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Enhancers in disease: molecular basis and emerging treatment strategies

Trends in Molecular Medicine, Год журнала: 2021, Номер 27(11), С. 1060 - 1073

Опубликована: Авг. 20, 2021

Enhancer disruption is increasingly implicated as a disease-driving mechanism. Chromosomal rearrangements can cause an enhancer to drive aberrant gene expression, genetic variants in enhancers impact transcription factor binding site, and disease-associated epigenetic changes are enriched regions.The three big challenges research focus on systematically identifying functional enhancers, their target genes, the context which they active.Bromo- extra-terminal (BET) inhibitors new class of drugs that inhibit expression. They under investigation treatment for cancer other diseases.Gene editing techniques elucidate function being used selectively regulate or mutate disturbed enhancers. Enhancers genomic sequences play key role regulating tissue-specific expression levels. An increasing number diseases linked impaired through chromosomal rearrangement, variation within modulation. Here, we review how these disruptions have recently been congenital disorders, cancers, common complex address implications diagnosis treatment. Although further fundamental into function, required, enhancer-targeting approaches show great therapeutic promise range diseases. Gene regulated by numerous factors, including polymerase recruitment, signaling, factors (TFs) (see Glossary) activity promoters regulatory genome affect nearby gene. The exact definition mechanism still matter active (Box 1). current view act recruiting specific TFs distal then activate involves physical contact with promoter (Figure 1A ). More recently, it has proposed form highly clusters (super stretch [1.Pott S. Lieb J.D. What super-enhancers?.Nat. Genet. 2015; 47: 8-12Crossref PubMed Scopus (330) Google Scholar]), may phase-separated assembly molecules [2.Hnisz D. et al.A phase separation model transcriptional control.Cell. 2017; 169: 13-23Abstract Full Text PDF (615) Scholar].Box 1Enhancer features, identificationEnhancers machinery subsequently forming loop region Figure main text) [87.Spitz F. Furlong E.E.M. Transcription factors: from developmental control.Nat. Rev. 2012; 13: 613-626Crossref (961) Scholar]. Chromatin spatially organized large domains called TADs, comprise smaller loops, enhancer–promoter loops [88.Dixon J.R. al.Topological mammalian genomes identified analysis chromatin interactions.Nature. 485: 376-380Crossref (3314) Scholar, 89.Krijger P.H.L. de Laat W. Regulation 3D genome.Nat. Mol. Cell Biol. 2016; 17: 771-782Crossref (124) 90.Nora E.P. al.Spatial partitioning landscape X-inactivation centre.Nature. 381-385Crossref (1527) 91.Rao S.S.P. map human at kilobase resolution reveals principles looping.Cell. 2014; 159: 1665-1680Abstract (2775) cohesin demarcates TAD boundaries forms extrusion its ring-shaped structure [92.Rao al.Cohesin loss eliminates all domains.Cell. 171: 305-320Abstract (629) Scholar,93.Schwarzer al.Two independent modes organization revealed removal.Nature. 551: 51-56Crossref (426) looping allows although most genes located linear chromosome [94.Furlong Levine M. Developmental topology.Science. 2018; 361: 1341-1345Crossref (168) effect debate, reviewed [89.Krijger Scholar,95.Ruiz-Velasco Zaugg J.B. Structure meets function: organisation conveys functionality.Curr. Opin. Syst. 1: 129-136Crossref On one hand, cohesin-mediated across cell lines correlate [96.Grubert al.Landscape genome.Nature. 2020; 583: 737-743Crossref (23) Scholar] mutations result [97.Liu N.Q. al.WAPL maintains loading cycle preserve cell-type-specific regulation.Nat. 2021; 53: 100-109Crossref (13) multiple studies shown do not translate [98.Ghavi-Helm Y. al.Highly rearranged chromosomes reveal uncoupling between topology expression.Nat. 2019; 51: 1272-1282Crossref (97) Scholar,99.Ing-Simmons E. al.Independence conformation regulation during Drosophila dorsoventral patterning.Nat. 487-499Crossref (0) Scholar].An sequence be validated experimentally measuring ability reporter plasmid [100.Arnold C.D. al.Genome-wide quantitative maps STARR-seq.Science. 2013; 339: 1074-1077Crossref (477) inserted [101.Inoue systematic comparison substantial differences versus episomal encoding activity.Genome Res. 27: 38-52Crossref (100) However, challenging investigate endogenous locus. Recent advances CRISPR methods started this inducing repressing elements loci [41.Schraivogel al.Targeted Perturb-seq enables genome-scale screens single cells.Nat. Methods. 629-635Crossref (17) Scholar,42.Dixit A. al.Perturb-seq: dissecting molecular circuits scalable single-cell RNA profiling pooled screens.Cell. 167: 1853-1866Abstract (464) Scholar,102.Fulco C.P. al.Activity-by-contact enhancer-promoter thousands perturbations.Nat. 1664-1669Crossref (110) A complementary approach predict based biochemical properties. characterized modifications like H3K4me1 H3K27ac [103.Spicuglia Vanhille L. signatures enhancers.Nucleus. 3: 126-131Crossref 104.Ong C.-T. Corces V.G. insights 2011; 12: 283-293Crossref (533) 105.Ernst J. Kellis ChromHMM: automating chromatin-state discovery characterization.Nat. 9: 215-216Crossref (1098) Active often flanked bidirectional capped RNAs, indicating both upstream downstream [84.Andersson R. al.An atlas types tissues.Nature. 507: 455-461Crossref (1282) Scholar,106.Kim T.-K. al.Enhancer RNAs: long noncoding RNAs synthesized enhancers.Cold Spring Harb. Perspect. 7a018622Crossref (82) Scholar].Enhancers Scholar]) shared type-specific regulation, yet clear if individual each separate whether mostly redundant [107.Miguel-Escalada I. al.Transcriptional enhancers: disease.Curr. Dev. 33: 71-76Crossref (16) Scholar,108.Bravo González-Blas C. al.Identification spatial integration transcriptomics epigenomics.Mol. 16e9438Crossref (12) Super seem particularly vulnerable structure, example, downregulating disturbing Scholar]: TFs, sequences, temporary links multi-molecular regulators drives cooperativity super Scholar,109.Boija al.Transcription phase-separation capacity activation 175: 1842-1855Abstract (428) Shortly after first was described rabbit hemoglobin β-1 [3.Banerji al.Expression beta-globin enhanced remote SV40 DNA sequences.Cell. 1981; 299-308Abstract (849) Scholar], evidence could lead disease humans found, misregulation β-globin translocation patients suffering β-thalassemia [4.Kioussis al.β-Globin inactivation γβ-thalassaemi.Nature. 1983; 306: 662-666Crossref Since then, enhanceropathies [5.Smith Shilatifard biology enhanceropathies.Nat. Struct. 21: 210-219Crossref (162) polydactyly caused 1 Mb away Sonic hedgehog [6.Lettice L.A. al.Disruption long-range cis-acting regulator Shh causes preaxial polydactyly.Proc. Natl. Acad. Sci. U. 2002; 99: 7548-7553Crossref IgH resulting overexpression MYC Burkitt's lymphoma [7.Taub al.Translocation c-myc immunoglobulin heavy chain locus Burkitt murine plasmacytoma cells.Proc. 1982; 79: 7837-7841Crossref With advent genome-wide association (GWAS) identify associations traits diseases, became majority trait-linked lie regions far promoters, thus likely targeting These associations, together enhancer-mediated mechanisms driving rare suggest way becoming next frontier drug identification. Structural induce 'enhancer hijacking' misplaced such regulates original targets [8.Northcott P.A. hijacking activates GFI1 family oncogenes medulloblastoma.Nature. 511: 428-434Crossref (312) This phenomenon cancer, where micro-amplification [9.Abraham B.J. al.Small insertions misregulate oncogenes.Nat. Commun. 8: 14385Crossref (38) oncogene (Table recent whole-genome sequencing profiles over 1200 found hundreds alterations were observed 100 kb structural breakpoint, some attributed [10.Zhang al.High-coverage 1220 cancers deregulated rearrangement-mediated cis-regulatory alterations.Nat. 11: 736Crossref (21) data indicate more than currently appreciate few examples. Yet dual challenge determining cancer-driving potential makes hard study.Table 1Examples diseaseaAbbreviations: CCNE1, cyclin E1; CpG, cytosine guanine nucleotide sequence; CSMD1, CUB Sushi Multiple Domains 1; CTCF, CCCTC-binding factor; FMR1, Fragile X Mental Retardation Protein GFI1, Growth Factor Independent GWAS, study; HOXA, Homeobox A; IGF2, insulin-like 2; LMO2, LIM Domain Only MEF2C, Myocyte 2C; PTF1A, Pancreas Associated 1A; RASGRP1, RAS Guanyl Releasing RET, Ret Proto-Oncogene; SNP, polymorphism; SOX9, SRY-Box 9; TAD, topologically associated domain; TBX5, T-Box 5; TF, ZBTB16, Zinc Finger And BTB Containing 16.Disruption mechanismPhenotypeDescriptionRefsEnhancer hijackingMedulloblastomaSomatic fusion GFI1B[8.Northcott Scholar]Enhancer hijacking(Pediatric) cancersAmplification MYCN local enhancers[113.Helmsauer K. determines extrachromosomal circular amplicon architecture neuroblastoma.Nat. 5823Crossref (7) hijackingSalivary gland acinic carcinomaRearrangements translocate NR4A3, TF upregulates genes[114.Haller oncogenic NR4A3 carcinomas salivary glands.Nat. 10: 368Crossref (61) hijackingMultiple cancers18 candidate events pan-cancer 98 tumor-type analyses (including IGF2 colorectal cancer)[115.Weischenfeldt al.Pan-cancer somatic copy-number implicates IRS4 hijacking.Nat. 49: 65-74Crossref (170) hijackingPrimary gastric adenocarcinomaRearrangements mistargeting CCNE1 IGF2[116.Ooi W.F. al.Integrated paired-end recurrent primary adenocarcinoma.Gut. 69: 1039-1052Crossref (9) hijackingT-lineage acute lymphoblastic leukaemiaTranslocations HOXA cluster[117.Yang al.3D identifies high-risk T-lineage leukemia.BioRxiv. (Published online Mach 12, 2020)https://doi.org/10.1101/2020.03.11.988279Google leukemiaSmall (e.g. LMO2) expression[9.Abraham Scholar]TAD boundary removalLimb malformationsTAD removed rearrangements, subsequent two Epha4 leading ectopic expression[12.Lupiáñez D.G. al.Disruptions topological pathogenic rewiring gene-enhancer interactions.Cell. 161: 1012-1025Abstract (941) removal5q14.3 microdeletion syndromeDisrupted leads decreased known gene[118.Redin al.The balanced cytogenetic abnormalities anomalies.Nat. 36-45Crossref removalFragile syndromeCTCF CGG triplet repeat near FMR1[13.Sun J.H. al.Disease-associated short tandem repeats co-localize domain boundaries.Cell. 224-238Abstract Scholar]Mutation enhancerPierre Robin syndromeMicrodeletion SOX9 nervous system skeletal structures[119.Benko conserved non-coding either side Pierre sequence.Nat. 2009; 41: 359-364Crossref (266) enhancerIsolated atrial defectsHomozygous point mutation 90 TBX5[120.Smemo al.Regulatory TBX5 isolated heart disease.Hum. 3255-3263Crossref (117) pancreatic agenesisMutations PTF1A enhancer[121.Weedon M.N. al.Recessive agenesis.Nat. 46: 61-64Crossref (166) enhancerIntellectual disabilityEnrichment novo fetal brain-specific identification CSMD1 affects neurogenesis[21.De Vas M.G. al.De brain significant severe intellectual disability.BioRxiv. April 28, 2019)https://doi.org/10.1101/621029Google Scholar]Enrichment SNPs enhancersCrohn's disease, sclerosis, electrocardiogram phenotypesCell enrichment GWAS DNase I hypersensitivity sites Th17, CD3+, cell, respectively[122.Maurano M.T. al.Systematic localization DNA.Science. 337: 1190-1195Crossref (1901) enhancersImmune diseases60% fine-mapped immune enhancers[123.Farh K.K-H. al.Genetic fine mapping causal autoimmune variants.Nature. 518: 337-343Crossref (964) enhancersType diabetesGWAS thymus, CD4+ CD8+ T cells, B CD34+ enhancers[124.Onengut-Gumuscu al.Fine type diabetes susceptibility colocalization lymphoid enhancers.Nat. 381-386Crossref (317) II islet regions[125.Pasquali al.Pancreatic 2 risk-associated variants.Nat. 136-143Crossref (303) enhancersImmunodeficiencyTwo influencing RASGRP1 levels autoimmunity-associated SNPs[126.Baars M.J.D.

Язык: Английский

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Surmounting cancer drug resistance: New insights from the perspective of N6-methyladenosine RNA modification

Drug Resistance Updates, Год журнала: 2020, Номер 53, С. 100720 - 100720

Опубликована: Авг. 20, 2020

Язык: Английский

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Regulation, functions and transmission of bivalent chromatin during mammalian development

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 24(1), С. 6 - 26

Опубликована: Авг. 26, 2022

Язык: Английский

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Clinical application of advanced multi-omics tumor profiling: Shaping precision oncology of the future

Cancer Cell, Год журнала: 2022, Номер 40(9), С. 920 - 938

Опубликована: Сен. 1, 2022

Язык: Английский

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Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 10, 2022

The mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated in cancer and inactivation results a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving high degree of selective inhibition likely essential to afford acceptable therapeutic index, realizing this objective challenging due the homology with paralog. Herein we report discovery potent proteolysis-targeting chimera molecule (PROTAC), A947. Selective degradation achieved absence SMARCA2/4 PROTAC binding translates vitro growth vivo efficacy mutant models, compared wild type models. Global ubiquitin mapping proteome profiling reveal no unexpected off-target related A947 treatment. Our study highlights ability transform non-selective SMARCA2/4-binding ligand into efficacious SMARCA2-targeting PROTAC, thereby provides potential new opportunity for patients whose tumors contain mutations.

Язык: Английский

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SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion

Cell, Год журнала: 2024, Номер 187(4), С. 861 - 881.e32

Опубликована: Янв. 31, 2024

Язык: Английский

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