Genetics and biology of prostate cancer

Genes & Development, Journal Year: 2018, Volume and Issue: 32(17-18), P. 1105 - 1140

Published: Sept. 1, 2018

Despite the high long-term survival in localized prostate cancer, metastatic cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by lack therapeutic regimens capable generating durable responses setting extreme tumor heterogeneity on genetic and cell biological levels. Here, we review available model systems, genome atlas, cellular functional microenvironment, tumor-intrinsic tumor-extrinsic mechanisms underlying resistance, technological advances focused detection management. These advances, along with an improved understanding adaptive to conventional therapies, anti-androgen therapy, immunotherapy, are catalyzing development more effective strategies for disease. In particular, knowledge heterotypic interactions between coevolution host cells microenvironment has illuminated novel combinations a strong potential eventual cures Improved management will also benefit from artificial intelligence-based expert decision support systems proper standard care, prognostic determinant biomarkers minimize overtreatment disease, new standards care accelerated next-generation clinical trials.

Language: Английский

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PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Sept. 9, 2020

The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and DNA damage response. PARP1 possesses activity when activated by damage, adds branched PAR chains to facilitate recruitment other repair proteins promote single-strand breaks. PARP inhibitors (PARPi) were first approved cancer drugs that specifically targeted response BRCA1/2 mutated breast ovarian cancers. Since then, there been significant advances our understanding mechanisms behind sensitization tumors expansion use PARPi treat several types. Here, we review recent proposed action PARPi, biomarkers tumor clinical therapy, potential combination therapies resistance.

Language: Английский

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DNA methylation: a historical perspective

Trends in Genetics, Journal Year: 2022, Volume and Issue: 38(7), P. 676 - 707

Published: April 30, 2022

5mC was discovered in mammals and found to have a nonrandom distribution that suggested possible biological function.In the early 1980s, DNA methylation within 5′ promoter regions, but not elsewhere, inhibit transcription of associated gene.Throughout 1990s 2000s, mechanisms gene regulation by were elucidated as well its relationship with histone modifications influence on 3D genome organization uncovered.Over past decade, high-throughput sequencing technologies complemented earlier single-gene efforts ultimately provided global understanding dynamics development disease. In 1925, 5-methylcytosine first reported bacteria. However, importance intuitive for several decades. After this initial lag, ubiquitous presence methylated base emerged across all domains life revealed range essential functions. Today, we are armed knowledge key factors establish, maintain, remove access staggering rapidly growing number base-resolution maps. Despite this, fundamental details about precise role interpretation patterns remain under investigation. Here, review field from beginning present day, an emphasis findings mammalian systems, point reader select experiments form foundation field. A quarter century ago, one pioneers methylation, Rudolf Jaenisch, outlined August 1997 issue Trends Genetics why should bother caring speculated which developmental contexts it might function [1.Jaenisch R. imprinting: bother?.Trends Genet. 1997; 13: 323-329Abstract Full Text PDF PubMed Scopus (313) Google Scholar]. would like still bother, what learned nearly research, need address coming years. Since discovery bacteria has been investigated vast organisms is linked topics organization, reproduction development, disease aging. It most well-studied epigenetic mechanism often used classical example inheritance, although recent advances shown modification be more dynamic, hence complex, than previously thought [2.Ginno P.A. et al.A genome-scale map turnover identifies site-specific dependencies DNMT TET activity.Nat. Commun. 2020; 11: 2680Crossref (45) Scholar, 3.Charlton J. al.TETs compete DNMT3 activity pluripotent cells at thousands somatic enhancers.Nat. 52: 819-827Crossref (34) 4.Spada F. al.Active genomic methylcytosine cells.Nat. Chem. Biol. 16: 1411-1419Google ever-growing body work published each year, remains difficult pinpoint genome. also unresolved differentiated, pluripotent, [5.Jackson-Grusby L. al.Loss causes p53-dependent apoptosis deregulation.Nat. 2001; 27: 31-39Crossref (558) 6.Chen T. al.Establishment maintenance mouse embryonic stem Dnmt3a Dnmt3b.Mol. Cell. 2003; 23: 5594-5605Crossref (560) 7.Tsumura A. al.Maintenance self-renewal ability absence methyltransferases Dnmt1, Dnmt3b.Genes Cells. 2006; 805-814Crossref (394) Scholar] altered into distinct landscape cancer types [8.Baylin S.B. Jones Epigenetic determinants cancer.Cold Spring Harb. Perspect. 2016; 8a019505Crossref (468) As typical articles design focus summarizing discoveries around their time [9.Jones Laird P.W. Cancer epigenetics comes age.Nat. 1999; 21: 163-167Crossref (2028) 10.Bird memory.Genes Dev. 2002; 6-21Crossref (5200) 11.Suzuki M.M. Bird landscapes: provocative insights epigenomics.Nat. Rev. 2008; 9: 465-476Crossref (2109) 12.Jones Liang G. Rethinking how maintained.Nat. 2009; 10: 805-811Crossref (537) 13.Law J.A. Jacobsen S.E. Establishing, maintaining modifying plants animals.Nat. 2010; 204-220Crossref (2344) 14.Smith Z.D. Meissner methylation: roles development.Nat. 2013; 14: (1783) 15.Du al.DNA pathways crosstalk methylation.Nat. Mol. Cell 2015; 519-532Crossref (494) 16.Lyko The methyltransferase family: versatile toolkit regulation.Nat. 2018; 19: 81-92Crossref (486) 17.Greenberg M.V.C. Bourc'his, D. diverse disease.Nat. 2019; 20: 590-607Crossref (533) 18.Parry during cell fate decisions.Nat. 2021; 22: 59-66Crossref (37) Scholar], decided complement providing systematic covering entire history highlight many foundational our current built. expected, primary literature vast, apologize having omit elegant summarize emergence progression century. At turn 20th century, Walter Sutton (1902) Theodore Boveri (1903) independently proposed chromosomal theory linking Gregor Mendel's (1866) long overlooked laws behavior inheritance own meiosis [19.Sutton W.S. On morphology chromosome group Brachystola magna.Biol. Bull. 1902; 4: 24-39Crossref Scholar,20.Sutton chromosomes heredity.Biol. 1903; 231-251Crossref This initially controversial gained credence following 1910 paper detractors, Thomas Hunt Morgan, who demonstrated eye color Drosophila melanogaster determined X chromosome, decisive piece evidence support [21.Morgan T.H. Sex limited Drosophila.Science. 1910; 32: 120-122Crossref Levene Jacobs' research nucleic acids they reside polymer chain nucleotides [22.Levene Jacobs W.A. Über die hefe-nucleinsäure.Ber. Dtsch. Ges. 1909; 42: 2474-2478Crossref (0) interest composition these laid among others epigenetics, central actor (Figure 1A ). Johnson Coghill isolated crystalized Mycobacterium tuberculosis effort identify pathogenic determinant. One candidates (5mC) (see Glossary), nucleotide had postulated occur naturally living based his previous success vitro biochemical synthesis [23.Wheeler H.L. Researches pyrimidine derivatives.J. Am. Soc. 1904; 31: 591-606Google Microscopic examination hydrolyzed acid picrate crystals polarized light indeed distinguished cytosine [24.Johnson T.B. R.D. pyrimidines. C111. 5-methyl-cytosine tuberculinic acid, tubercle bacillus.J. 1925; 47: 2838-2844Crossref seemingly relevant discovery, next report only 23 years later. Using chromatography [25.Vischer E. Chargaff separation characterization purines minute amounts hydrolysates.J. 1947; 168: 781Abstract Hotchkiss observed faint band near chromatograph calf thymus behaved cytosine, yet slightly shifted migration, leading him suggest some therefore labeled 'epi-cytosine' [26.Hotchkiss quantitative purines, pyrimidines, nucleosides chromatography.J. 1948; 175: 315-332Abstract 1B). Specifically, he noted epi-cytosine relates terms absorption spectrum mobility same manner thymine uracil. 5-methyluracil, inferred could possibly 5mC. Two later, Wyatt confirmed mammalian, insect, plant broad quantities [27.Wyatt G.R. Occurrence acids.Nature. 1950; 166: 237-238Crossref Scholar,28.Wyatt Recognition estimation acids.Biochem. 1951; 48: 581-584Crossref carriers genetic information [29.Avery O.T. al.Studies chemical nature substance inducing transformation pneumococcal types.J. Exp. Med. 1944; 79: 137-158Crossref Scholar,30.Hershey B.A.D. Chase M. Independent functions viral protein growth bacteriophage.J. Gen. Physiol. 1952; 36: 39-56Crossref structure double helix [31.Watson J.D. Crick F.H.C. Molecular acids: deoxyribose acid.Nature. 1953; 171: 737-738Crossref (7945) grew. Sinsheimer subsequently randomly distributed specifically CpG dinucleotide context 1C). Interestingly, doublet frequently expected eukaryotic [32.Smith Markham Polynucleotides deoxyribonucleic 170: 120-121Crossref Scholar,33.Sinsheimer R.L. al.The action pancreatic desoxyribonuclease. I. Isolation mono- dinucleotides.J. 1954; 208: 445-459Abstract Why did take so before started progress rapidly? obvious reason historical discovery. know chains carry information. 1928 Frederick Griffith [34.Griffith significance Hyg. 1928; 113-159Crossref 1944 Avery-MacLeod-McCarty experiment conclusion Second World War, 1952 Hershey-Chase [30.Hershey resolution helped lay needed enabled exploration relevance DNA. additional may caused hesitation: other groups find isolates Scholar,35.Vischer Ernst al.Microbial desoxypentose avian bacilli yeast.J. 1949; 177: 429-438Abstract low abundance seemed disqualifying major function. aside, worth mentioning parallel experimental advances, biologist Conrad Waddington coined term 'epigenetics' 1942 [36.Waddington C.H. epigenotype.Endeavour. 1942; 1: 18-20Crossref widely 1957 [37.Waddington Strategy Genes; Discussion Some Aspects Theoretical Biology. Allen & Unwin, 1957Google Scholar]; however, concepts until became clearer over subsequent dawn molecular biology set stage thorough investigation appreciation mammals. made studying [38.Borek Srinivasan P.R. acids.Annu. Biochem. 1966; 35: 275-298Crossref tractable abundant model organism, prokaryotes thereby paved way study higher 2A Luria, Bertani, Weigle different families bacteriophage diverge infect certain bacterial strains [39.Luria Mutations viruses affecting host range.Genetics. 1945; 30: 84-99PubMed Scholar,40.Bertani J.J. Host controlled variation viruses.J. Bacteriol. 65: 113-121Crossref basis strain specificity infection due phage's differential enter strains, rather because once inside, incompatible phage degraded immune-like response [41.Lederberg S. Suppression multiplication heterologous bacteriophages lysogenic bacteria.Virology. 1957; 3: 496-513Google mechanistic advance strain-specific activity, raised possibility defense against phages [42.Gold enzymatic RNA DNA, II. species enzymes.Proc. Natl. Acad. Sci. U. 1963; 50: 164-169Crossref Thus, Arber restriction system (R-M system) where methylation-sensitive 'restriction enzymes' defend invading digesting Bacterial protected enzymes species-specific [43.Arber W. Host-controlled bacteriophage.Annu. Microbiol. 1965; 365-378Crossref Beyond protection, link between replication [44.Billen Hewitt Influence starvation methionine amino replication.J. 92: 609-617Google Billen normal Escherichia coli growth, evident behind fork exclusively placed unmethylated nascent strand 2B). methionine, methyl donor, led strand, retained get after S phase when added back media [45.Billen Methylation chromosome: event "replication point"?.J. 1968; 477-486Crossref cannot serve template round [46.Lark C. Studies vivo 15T.J. 389-399Crossref deficient methyl-donor showed degradation [47.Lark produced coli.J. 1970; 337-348Crossref 1964 modifications, Borek plays defining bacteria, similar act eukaryotes underlie type diversity [48.Srinivasan Enzymatic alteration structure: put finishing touches characteristic insertion groups.Science. 1964; 145: 548-553Crossref Four nuclear extracts tissues adult rat tested methylate various species. extracts, such kidney or liver, harbor potent brain spleen extracts. Based observations, organism content [49.Sheid B. al.Deoxyribonucleic methylase tissues.Biochemistry. 7: 280-285Crossref gleaned studies basics immunity replication, though remained unclear whether any conserved organisms. responsible adding cytosines polymers. regulated, thus path specific target modification. particular, tissue-specific rodents intriguing, data too sparse draw meaningful conclusions yet. Once clear 5mC, despite relatively abundance, does play general regulatory credibility. fields, important technological enable informative theoretical models decade. plants, indicated widespread modification, further using mass spectrometry. 1970s, Vanyushin quantified levels animals, including sponges, mollusks, sea urchins, bony fish, amphibians, reptiles, [50.Vanyushin B.F. al.Rare bases animal DNA.Nature. 225: 948-949Crossref (290) Scholar,51.Vanyushin DNA: tissue specificity.Biochim. Biophys. Acta. 1973; 299: 397-403Crossref These analyses while both GC can differ species, closely related generally comparable tissues. later sequence varying [52.Guseinov V.A. Content localisation healthy wilt-infected cotton plants.Biochim. Acta (BBA) - Nucleic Acids Protein Synth. 1975; 395: 229-238Google reports profiling spectrometry accumulated, organisms, that: (i) no [53.Adams R.L.P. fibroblasts.Biochim. 1971; 254: 205-212Crossref Scholar,54.Adams Delayed developing urchin embryos.Nat. New 244: 27-29Crossref (ii) guide mutations, required transcriptional changes [55.Scarano control differentiation embryogenesis.Adv. Cytopharmacolo. 13-24PubMed (iii) activator [56.Comings D.E. euchromatic heterochromatic DNA.Exp. Res. 1972; 74: 383-390Crossref (Box 1). 1975, three notable reviews unique frameworks contemplating investigating effects [57.Holliday Pugh J.E. development.Science. 187: 226-232Crossref (1302) 58.Riggs A.D. inactivation, differentiation, methylation.Cytogenet. 9-25Crossref 59.Sager Kitchin Selective silencing DNA.Science. 189: 426-433Crossref While differed specific, rationalized mechanisms, fundamentally agreed regulating expression orchestrating development.Box 1Early theories methylationWork prior 1970s scientists propose formal hypotheses eukaryotes. late 1960s, Scarano colleagues 90% CG them speculate [277.Scarano heterogeneity origin isostichs embryos.Proc. 1967; 57: 1394-1400Crossref Scholar,278.Grippo P. al.Methylation embryos.J. 195-208Crossref 1971, spontaneous deamination generates C→T conversion, lead heritable sequence. popular 1960s up 1980s mutations genes direct differentiation. 5mC-guided mutation cellular embryogenesis Scholar].In Adams' patterning fibroblasts replicating quickly, takes hours become fully methylated. observation active occurs predominantly S-phase Adams conclude must controlling His influenced Lark implicated regulator Scholar,46.Lark 1972 Comings came looking Chinese hamster ovarian cells, AT-rich undermethylated greater extent composition, GC-rich highly if high transcription, then CG→TA actively selected euchromatin To Comings, idea enriched regions activator.In 1973, twice pluteus morula [54.Adams agreement suggesting urchins gastrulation [278.Grippo Scholar,279.Comb D.G. embryo development.J. 851-855Crossref quantify stage, revise regulate instead new 'switch off' contributing development. Work

Language: Английский

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Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs

Nature Cell Biology, Journal Year: 2018, Volume and Issue: 20(5), P. 535 - 540

Published: April 19, 2018

Language: Английский

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Eukaryotic 5-methylcytosine (m5C) RNA Methyltransferases: Mechanisms, Cellular Functions, and Links to Disease

Genes, Journal Year: 2019, Volume and Issue: 10(2), P. 102 - 102

Published: Jan. 30, 2019

5-methylcytosine (m⁵C) is an abundant RNA modification that's presence reported in a wide variety of species, including cytoplasmic and mitochondrial ribosomal RNAs (rRNAs) transfer (tRNAs), as well messenger (mRNAs), enhancer (eRNAs) number non-coding RNAs. In eukaryotes, C5 methylation cytosines catalyzed by enzymes the NOL1/NOP2/SUN domain (NSUN) family, DNA methyltransferase homologue DNMT2. recent years, substrate target nucleotides for each these methyltransferases have been identified, structural biochemical analyses provided first insights into how achieves specificity. Functional characterizations proteins modifications they install revealed important roles diverse aspects both nuclear gene expression. Importantly, this knowledge has enabled better understanding molecular basis diseases caused mutations genes encoding m⁵C or changes expression level enzymes.

Language: Английский

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Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy

European Journal of Pharmacology, Journal Year: 2018, Volume and Issue: 837, P. 8 - 24

Published: Aug. 18, 2018

Language: Английский

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Epidrugs: targeting epigenetic marks in cancer treatment

Epigenetics, Journal Year: 2019, Volume and Issue: 14(12), P. 1164 - 1176

Published: July 6, 2019

Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis cancer. Unlike genetic mutations, ability reprogram landscape in cancer epigenome one most promising target therapies both treatment and reversibility drug resistance. Epigenetic alterations development progression may be basis for individual variation response. Thus, this review focuses on emerging area pharmaco(epi)genomics, specifically highlighting reprogramming during tumorigenesis how markers are targeted as a therapy (epidrugs) clinical implications treatment.

Language: Английский

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Role of Mammalian DNA Methyltransferases in Development

Annual Review of Biochemistry, Journal Year: 2019, Volume and Issue: 89(1), P. 135 - 158

Published: Dec. 9, 2019

DNA methylation at the 5-position of cytosine (5mC) plays vital roles in mammalian development. is catalyzed by methyltransferases (DNMTs), and two DNMT families, DNMT3 DNMT1, are responsible for establishment maintenance, respectively. Since their discovery, biochemical structural studies have revealed key mechanisms underlying how DNMTs catalyze de novo maintenance methylation. In particular, recent development low-input genomic epigenomic technologies has deepened our understanding regulation germ lines early stage embryos. this review, we first describe machinery including essential cofactors. We then discuss recruited to or excluded from certain elements. Lastly, summarize dynamics embryos with a focus on both mice humans.

Language: Английский

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Transcriptional and Epigenomic Regulation of Adipogenesis

Molecular and Cellular Biology, Journal Year: 2019, Volume and Issue: 39(11)

Published: March 29, 2019

Understanding adipogenesis, the process of adipocyte development, may provide new ways to treat obesity and related metabolic diseases. Adipogenesis is controlled by coordinated actions lineage-determining transcription factors epigenomic regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) C/EBPα are master "adipogenic" factors. In recent years, a growing number studies have reported identification novel transcriptional regulators adipogenesis. However, many these not been validated in development vivo their working mechanisms often far from clear. this minireview, we discuss advances regulation with focus on shared both white adipogenesis brown Studies highlight importance investigating differentiation rather than drawing conclusions based knockdown experiments cell culture. Advances understanding revealed critical roles histone methylation/demethylation, acetylation/deacetylation, chromatin remodeling, DNA methylation, microRNAs differentiation. We also future research directions that help identify regulating

Language: Английский

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Chemical and Biochemical Perspectives of Protein Lysine Methylation

Chemical Reviews, Journal Year: 2018, Volume and Issue: 118(14), P. 6656 - 6705

Published: June 21, 2018

Protein lysine methylation is a distinct posttranslational modification that causes minimal changes in the size and electrostatic status of residues. Lysine plays essential roles regulating fates functions target proteins an epigenetic manner. As result, substrates degrees (free versus mono/di/tri) protein are orchestrated within cells by balanced activities methyltransferases (PKMTs) demethylases (KDMs). Their dysregulation often associated with neurological disorders, developmental abnormalities, or cancer. Methyllysine-containing can be recognized downstream effector proteins, which contain methyllysine reader domains, to relay their biological functions. While numerous efforts have been made annotate methylation, limited work has done uncover mechanisms this at molecular atomic level. Given biophysical biochemical properties methyllysine, review will focus on chemical aspects addition, recognition, removal mark. Chemical methods profile PKMT discussed along classification inhibitors for accurate perturbation methyltransferase activities. Semisynthesis methyllysine-containing also covered given critical need these reagents unambiguously define functional methylation.

Language: Английский

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