Skip to main content

Advertisement

SpringerLink
Log in

Targeting epigenetics using synthetic lethality in precision medicine

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Technological breakthroughs in genomics have had a significant impact on clinical therapy for human diseases, allowing us to use patient genetic differences to guide medical care. The “synthetic lethal approach” leverages on cancer-specific genetic rewiring to deliver a therapeutic regimen that preferentially targets malignant cells while sparing normal cells. The utility of this system is evident in several recent studies, particularly in poor prognosis cancers with loss-of-function mutations that become “treatable” when two otherwise discrete and unrelated genes are targeted simultaneously. This review focuses on the chemotherapeutic targeting of epigenetic alterations in cancer cells and consolidates a network that outlines the interplay between epigenetic and genetic regulators in DNA damage repair. This network consists of numerous synergistically acting relationships that are druggable, even in recalcitrant triple-negative breast cancer. This collective knowledge points to the dawn of a new era of personalized medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

HR:

Homologous recombination

NHEJ:

Non-homologous end joining

MMEJ:

Microhomology-mediated end joining

HDAC:

Histone deacetylase

HDAC:

Histone deacetylase inhibitor

DSB:

Double-stranded DNA break

PARP:

Poly (ADP-ribose) polymerase

PARPi:

Poly (ADP-ribose) polymerase inhibitor

PRC:

Polycomb repressive complex

miRNA:

Micro-RNA

siRNA:

Small interference-RNA

LncRNA:

Long non-coding RNA

RNAi:

RNA interference

H3K4:

Histone H3 lysine 4

H3K4me:

Methylated histone H3 lysine 4

H3K27me:

Methylated histone H3 lysine 27

H3K36me:

Methylated histone H3 lysine 36

SAHA:

Suberoylanilide hydroxamic acid

PARylation:

Poly ADP ribosylation

References

  1. De Iuliis F, Salerno G, Taglieri L, Scarpa S (2015) Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Cancer Chemother Pharmacol 76:679–690. https://doi.org/10.1007/s00280-015-2818-4

    Article  PubMed  CAS  Google Scholar 

  2. Roscilli G et al (2016) Human lung adenocarcinoma cell cultures derived from malignant pleural effusions as model system to predict patients chemosensitivity. J Transl Med 14:61. https://doi.org/10.1186/s12967-016-0816-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Tremblay J, Hamet P (2013) Role of genomics on the path to personalized medicine. Metabolism 62:S2–S5. https://doi.org/10.1016/j.metabol.2012.08.023

    Article  PubMed  CAS  Google Scholar 

  4. Lionetti M, Neri A (2017) Utilizing next-generation sequencing in the management of multiple myeloma. Expert Rev Mol Diagn 17:653–663. https://doi.org/10.1080/14737159.2017.1332996

    Article  PubMed  CAS  Google Scholar 

  5. Weitzel KW et al (2016) IGNITE network. The IGNITE network: a model for genomic medicine implementation and research. BMC Med Genomics 9:1. https://doi.org/10.1186/s12920-015-0162-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Inaba H, Azzato EM, Mullighan CG (2017) Integration of next-generation sequencing to treat acute lymphoblastic leukemia with targeted lesions: the St. Jude Children’s Research Hospital Approach. Front Pediatr 5:258. https://doi.org/10.3389/fped.2017.00258

    Article  PubMed  PubMed Central  Google Scholar 

  7. Weinstein IB (2000) Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21:857–864

    Article  PubMed  CAS  Google Scholar 

  8. Rowley JD (1973) A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–303

    Article  PubMed  CAS  Google Scholar 

  9. Hannah AL (2005) Kinases drug discovery targets in hematologic malignancies. Curr Mol Med 5:625–642

    Article  PubMed  CAS  Google Scholar 

  10. Tolbert VP, Coggins GE, Maris JM (2017) Genetic susceptibility to neuroblastoma. Curr Opin Genet Dev 42:81–90. https://doi.org/10.1016/j.gde.2017.03.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Karlic H, Schlögl EE, Nowotny H, Grüner H, Valent A, Auer H, Heinz R (1994) Rare occurrence of Philadelphia chromosome negative (but BCR-ABL positive) CML in a central European population. Am J Hematol 47:253–254

    Article  PubMed  CAS  Google Scholar 

  12. Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC (2012) ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients. Mod Pathol 25:1516–1525. https://doi.org/10.1038/modpathol.2012.107

    Article  PubMed  CAS  Google Scholar 

  13. Nijman SMB (2011) Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett 585:1–6. https://doi.org/10.1016/j.febslet.2010.11.024

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Jackson RA, Chen ES (2016) Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs. Pharmacol Ther 162:69–85. https://doi.org/10.1016/j.pharmathera.2016.01.014

    Article  PubMed  CAS  Google Scholar 

  15. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917

    Article  PubMed  CAS  Google Scholar 

  16. Farmer H et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  PubMed  CAS  Google Scholar 

  17. Oike T et al (2013) A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res 73:5508–5518. https://doi.org/10.1158/0008-5472.CAN-12-4593

    Article  PubMed  CAS  Google Scholar 

  18. Hoffman GR et al (2014) Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc Natl Acad Sci USA 111:3128–3133. https://doi.org/10.1073/pnas.1316793111

    Article  PubMed  CAS  Google Scholar 

  19. Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, Pollard JR (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7:428–430. https://doi.org/10.1038/nchembio.573

    Article  PubMed  CAS  Google Scholar 

  20. Menezes DL et al (2015) A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol Cancer Res 13:120–129. https://doi.org/10.1158/1541-7786.MCR-14-0240

    Article  PubMed  CAS  Google Scholar 

  21. Manic G, Obrist F, Sistigu A, Vitale I (2015) Trial watch: targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy. Mol Cell Oncol 2:e1012976. https://doi.org/10.1080/23723556.2015.1012976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Min A et al (2017) AZD6738, a novel inhibitor of ATR induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol Cancer Ther 16:566–577. https://doi.org/10.1158/1535-7163.MCT-16-0378

    Article  PubMed  CAS  Google Scholar 

  23. Schmitt A et al (2017) ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma. Cancer Res 77:3040–3056. https://doi.org/10.1158/0008-5472.CAN-16-3398

    Article  PubMed  CAS  Google Scholar 

  24. Menezes DL et al (2015) A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol Cancer Res 13:120–129. https://doi.org/10.1158/1541-7786.MCR-14-0240

    Article  PubMed  CAS  Google Scholar 

  25. Zhang XY et al (2011) Inhibition of the single downstream target BAG1 activates the latent apoptotic potential of MYC. Mol Cell Biol 31:5037–5045. https://doi.org/10.1128/MCB.06297-11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Martin SE, Wu ZH, Gehlhaus K, Jones TL, Zhang YW, Guha R, Miyamoto S, Pommier Y, Caplen NJ (2011) RNAi screening identifies TAK1 as a potential target for the enhanced efficacy of topoisomerase inhibitors. Curr Cancer Drug Targets 11:976–986

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. van Pel DM, Stirling PC, Minaker SW, Sipahimalani P, Hieter P (2013) Saccharomyces cerevisiae genetics predicts candidate therapeutic genetic interactions at the mammalian replication fork. G3 (Bethesda) G3:273–282. https://doi.org/10.1534/g3.112.004754

    Article  CAS  Google Scholar 

  28. Nguyen TT et al (2016) Predicting chemotherapeutic drug combinations through gene network profiling. Sci Rep 6:18658. https://doi.org/10.1038/srep18658

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Tay Z et al (2014) P-glycoprotein and vacuolar ATPase synergistically confer anthracycline resistance to fission yeast and human cells. Curr Med Chem 21:251–260

    Article  PubMed  CAS  Google Scholar 

  30. Tay Z, Eng RJ, Sajiki K, Lim KK, Tang MY, Yanagida M, Chen ES (2013) Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast. PLoS One 8:e55041. https://doi.org/10.1371/journal.pone.0055041

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Allis CD, Jenuwein T, Reinberg D, Caparros ML (eds) (2006) Epigenetics. Cold Spring Harbor Laboratory Press, Woodbury, New York

    Google Scholar 

  32. Allis CD, Jenuwein T (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17:487–500. https://doi.org/10.1038/nrg.2016.59

    Article  PubMed  CAS  Google Scholar 

  33. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14:1025–1040. https://doi.org/10.1038/nsmb1338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Jeltsch A, Jurkowska RZ (2014) New concepts in DNA methylation. Trends Biochem Sci 39:310–318. https://doi.org/10.1016/j.tibs.2014.05.002

    Article  PubMed  CAS  Google Scholar 

  35. Zhou CY, Johnson SL, Gamarra NI, Narlikar GJ (2016) Mechanisms of ATP-dependent chromatin remodelling motors. Annu Rev Biophys 45:153–181. https://doi.org/10.1146/annurev-biophys-051013-022819

    Article  PubMed  CAS  Google Scholar 

  36. Clapier CR, Cairns BR (2009) The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273–304. https://doi.org/10.1146/annurev.biochem.77.062706.153223

    Article  PubMed  CAS  Google Scholar 

  37. Morris KV (2008) RNA-mediated transcriptional gene silencing in human cells. Curr Top Microbiol Immunol 320:211–224

    PubMed  CAS  Google Scholar 

  38. Chitwood DH, Timmermans MC (2010) Small RNAs are on the move. Nature 467:415–419. https://doi.org/10.1038/nature09351

    Article  PubMed  CAS  Google Scholar 

  39. Sun M et al (2016) LncRNA HOXA11-AS Promotes proliferation and invasion of gastric cancer by scaffolding the chromatin modification factors PRC2, LSD1, and DNMT1. Cancer Res 76:6299–6310

    Article  PubMed  CAS  Google Scholar 

  40. O’Leary VB, Hain S, Maugg D, Smida J, Azimzadeh O, Tapio S, Ovsepian SV, Atkinson MJ (2017) Long non-coding RNA PARTICLE bridges histone and DNA methylation. Sci Rep 7:1790. https://doi.org/10.1038/s41598-017-01875-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Wang C, Wang L, Ding Y, Lu X, Zhang G, Yang J, Zheng H, Wang H, Jiang Y, Xu L (2017) LncRNA structural characteristics in epigenetic regulation. Int J Mol Sci. https://doi.org/10.3390/ijms18122659

    Article  PubMed  PubMed Central  Google Scholar 

  42. Choudhuri S, Cui Y, Klaassen CD (2010) Molecular targets of epigenetic regulation and effectors of environmental influences. Toxicol Appl Pharmacol 245:378–393. https://doi.org/10.1016/j.taap.2010.03.022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254

    Article  PubMed  CAS  Google Scholar 

  44. Chen ES, Zhang K, Nicolas E, Cam HP, Zofall M, Grewal SI (2008) Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature 451:734–737. https://doi.org/10.1038/nature06561

    Article  PubMed  CAS  Google Scholar 

  45. Williams BP, Gehring M (2017) Stable transgenerational epigenetic inheritance requires a DNA methylation-sensing circuit. Nat Commun 8:2124. https://doi.org/10.1038/s41467-017-02219-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Brunner AM, Nanni P, Mansuy IM (2014) Epigenetic marking of sperm by post-translational modification of histones and protamines. Epigenetics Chromatin 7:2. https://doi.org/10.1186/1756-8935-7-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  PubMed  CAS  Google Scholar 

  48. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Wang CC, Song J, Wang Z, Dormann HL, Casadio F, Li H, Luo JL, Patel DJ, Allis CD (2009) Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459:847–851. https://doi.org/10.1038/nature08036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Chi P, Allis CD, Wang GG (2010) Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10:457–469. https://doi.org/10.1038/nrc2876

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Anjanappan M et al (2018) A system for detecting high impact-low frequency mutations in primary tumors and metastases. Oncogene 37:185–196. https://doi.org/10.1038/onc.2017.322

    Article  CAS  Google Scholar 

  52. Wan L et al (2017) ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 543:265–269. https://doi.org/10.1038/nature21687

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Kandoth C et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339. https://doi.org/10.1038/nature12634

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Stephens PJ et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486:400–404. https://doi.org/10.1038/nature11017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Fujimoto A et al (2012) Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 44:760–764. https://doi.org/10.1038/ng.2291

    Article  PubMed  CAS  Google Scholar 

  56. Varela I et al (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469:539–542. https://doi.org/10.1038/nature09639

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Dalgliesh GL et al (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463:360–363. https://doi.org/10.1038/nature08672

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Johann PD et al (2016) Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29:379–393. https://doi.org/10.1016/j.ccell.2016.02.001

    Article  PubMed  CAS  Google Scholar 

  59. Pugh TJ et al (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488:106–110. https://doi.org/10.1038/nature11329

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Yamane K, Mizugichi T, Cui B, Zofall M, Noma K, Grewal SI (2011) Asf1/HIRA facilitate global histone deacetylation and associate with HP1 to promote nucleosome occupancy at heterochromatic loci. Mol Cell 41:56–66. https://doi.org/10.1016/j.molcel.2010.12.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Nicolas E, Yamada T, Cam HP, Fitzgerald PC, Kobayashi R, Grewal SI (2007) Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection. Nat Struct Mol Biol 14:372–380

    Article  PubMed  CAS  Google Scholar 

  62. Kadoch C, Crabtree GR (2015) Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci Adv 1:e1500447. https://doi.org/10.1126/sciadv.1500447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Oike T, Ogiwara H, Amornwichet N, Nakano T, Kohno T (2014) Chromatin-regulating proteins as targets for cancer therapy. J Radiat Res 55:613–628. https://doi.org/10.1093/jrr/rrt227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Matsubara D et al (2013) Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. Cancer Sci 104:266–273. https://doi.org/10.1111/cas.12065

    Article  PubMed  CAS  Google Scholar 

  65. Rao Q, Xia QY, Shen Q, Shi SS, Tu P, Shi QL, Zhou XJ (2014) Coexistent loss of INI1 and BRG1 expression in a rhabdoid renal cell carcinoma (RCC): implications for a possible role of SWI/SNF complex in the pathogenesis of RCC. Int J Clin Exp Pathol 7:1782–1787

    PubMed  PubMed Central  Google Scholar 

  66. Karnezis AN et al (2016) Dual loss of the SWI/SNF complex ATPase SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J Pathol 238:389–400. https://doi.org/10.1002/path.4633

    Article  PubMed  CAS  Google Scholar 

  67. Raab JR, Runge JS, Spear CC, Magnuson T (2017) Co-regulation of transcription by BRG1 and BRM, two mutually exclusive SWI/SNF ATPase subunits. Epigenetics Chromatin 10:62. https://doi.org/10.1186/s13072-017-0167-8

    Article  PubMed  PubMed Central  Google Scholar 

  68. Sena JA, Wang L, Hu CJ (2013) BRG1 and BRM chromatin-remodeling complexes regulate the hypoxia response by acting as coactivators for a subset of hypoxia-inducible transcription factor target genes. Mol Cell Biol 33:3849–3863. https://doi.org/10.1128/MCB.00731-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lan J, Li H, Luo X, Hu J, Wang G (2017) BRG1 promotes VEGF-A expression and angiogenesis in human colorectal cancer cells. Exp Cell Res 360:236–242. https://doi.org/10.1016/j.yexcr.2017.09.013

    Article  PubMed  CAS  Google Scholar 

  70. Marquez-Vilendrer SB, Rai SK, Gramling SJ, Lu L, Reisman DN (2016) BRG1 and BRM loss selectively impacts RB and P53, respectively: BRG1 and BRM have differential functions in vivo. Oncoscience 3:337–350. https://doi.org/10.18632/oncoscience.333

    Article  PubMed  PubMed Central  Google Scholar 

  71. Vélez-Cruz R, Manickavinayaham S, Biswas AK, Clary RW, Premkumar T, Cole F, Johnson DG (2016) RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1. Genes Dev 30:2500–2512

    Article  PubMed  PubMed Central  Google Scholar 

  72. Vangamudi B et al (2015) The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNF-mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res 75:3865–3878. https://doi.org/10.1158/0008-5472.CAN-14-3798

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Wang X, Nagl NG, Wilsker D, Van Scoy M, Pacchione S, Yaciuk P, Dallas PB, Moran E (2004) Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem J 383:319–325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Wiegand KC et al (2010) ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 363:1532–1543. https://doi.org/10.1056/NEJMoa1008433

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Jones S et al (2010) Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330:228–231. https://doi.org/10.1126/science.1196333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Bitler BG et al (2015) Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 21:231–238. https://doi.org/10.1038/nm.3799

    Article  PubMed  CAS  Google Scholar 

  77. Kelso TWR, Porter DK, Amaral ML, Shokhirev MN, Benner C, Hargreaves DC (2017) Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers. Elife. https://doi.org/10.7554/elife.30506 (Epub before print)

    Article  PubMed  PubMed Central  Google Scholar 

  78. Sausen M et al (2013) Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45:12–17. https://doi.org/10.1038/ng.2493

    Article  PubMed  CAS  Google Scholar 

  79. Hodis E et al (2012) A landscape of driver mutations in melanoma. Cell 150:251–263. https://doi.org/10.1016/j.cell.2012.06.024

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Coatham M et al (2016) Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas. Mod Pathol 29:1586–1593. https://doi.org/10.1038/modpathol.2016.156

    Article  PubMed  CAS  Google Scholar 

  81. Helming KC et al (2014) ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med 20:251–254. https://doi.org/10.1038/nm.3480

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Simon JA, Kingston RE (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10:697–708. https://doi.org/10.1038/nrm2763

    Article  PubMed  CAS  Google Scholar 

  83. Varambally S et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629

    Article  PubMed  CAS  Google Scholar 

  84. Kleer CG et al (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 100:11606–11611

    Article  PubMed  CAS  Google Scholar 

  85. He LJ, Cai MY, Xu GL, Li JJ, Weng ZJ, Xu DZ, Luo GY, Zhu SL, Xie D (2012) Prognostic significance of overexpression of EZH2 and H3k27me3 proteins in gastric cancer. Asian Pac J Cancer Prev 13:3173–3178

    Article  PubMed  Google Scholar 

  86. Behrens C et al (2013) EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res 19:6556–6565. https://doi.org/10.1158/1078-0432.CCR-12-3946

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Lu C et al (2010) Regulation of tumor angiogenesis by EZH2. Cancer Cell 18:185–197. https://doi.org/10.1016/j.ccr.2010.06.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Toll AD, Dasgupta A, Potoczek M, Yeo CJ, Kleer CG, Brody JR, Witkiewicz AK (2010) Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma. Hum Pathol 41:1205–1209. https://doi.org/10.1016/j.humpath.2010.03.004

    Article  PubMed  CAS  Google Scholar 

  89. Wagener N, Macher-Goeppinger S, Pritsch M, Hüsing J, Hoppe-Seyler K, Schirmacher P, Pfitzenmaier J, Haferkamp A, Hoppe-Seyler F, Hohenfellner M (2010) Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer 10:524. https://doi.org/10.1186/1471-2407-10-524

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Cao W, Feng Z, Cui Z, Zhang C, Sun Z, Mao L, Chen W (2012) Up-regulation of enhancer of zeste homolog 2 is associated positively with cyclin D1 overexpression and poor clinical out- come in head and neck squamous cell carcinoma. Cancer 118:2858–2871. https://doi.org/10.1002/cncr.26575

    Article  PubMed  CAS  Google Scholar 

  91. Ernst T et al (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42:722–726. https://doi.org/10.1038/ng.621

    Article  PubMed  CAS  Google Scholar 

  92. Nikoloski G et al (2010) Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 42:665–667. https://doi.org/10.1038/ng.620

    Article  PubMed  CAS  Google Scholar 

  93. Knutson SK et al (2013) Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci USA 110:7922–7927. https://doi.org/10.1073/pnas.1303800110

    Article  PubMed  Google Scholar 

  94. Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD, Orkin SH (2013) Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 9:643–650. https://doi.org/10.1038/nchembio.1331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. McCabe MT et al (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–112. https://doi.org/10.1038/nature11606

    Article  PubMed  CAS  Google Scholar 

  96. Knutson SK et al (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8:890–896. https://doi.org/10.1038/nchembio.1084

    Article  PubMed  CAS  Google Scholar 

  97. Qi W et al (2012) Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci USA 109:21360–21365. https://doi.org/10.1073/pnas.1210371110

    Article  PubMed  Google Scholar 

  98. Gehling VS et al (2015) Discovery, design, and synthesis of indole-based EZH2 inhibitors. Bioorg Med Chem Lett 25:3644–3649. https://doi.org/10.1016/j.bmcl.2015.06.056

    Article  PubMed  CAS  Google Scholar 

  99. Honma D et al (2017) Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci 108:2069–2078. https://doi.org/10.1111/cas.13326

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Takano M, Tsuda H, Sugiyama T (2012) Clear cell carcinoma of the ovary: is there a role of histology-specific treatment? J Exp Clin Cancer Res 31:53. https://doi.org/10.1186/1756-9966-31-53

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Fujiwara K, Shintani D, Nishikawa T (2016) Clear-cell carcinoma of the ovary. Ann Oncol 27(Suppl 1):i50–i52. https://doi.org/10.1093/annonc/mdw086

    Article  PubMed  Google Scholar 

  102. Kim KH et al (2015) SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med 21:1491–1496. https://doi.org/10.1038/nm.3968

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Fillmore CM et al (2015) EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature 520:239–242. https://doi.org/10.1038/nature14122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Siddique HR, Saleem M (2012) Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells 30:372–378. https://doi.org/10.1002/stem.1035

    Article  PubMed  CAS  Google Scholar 

  105. Jin X et al (2017) Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. Nat Med 23:1352–1361. https://doi.org/10.1038/nm.4415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Wagner E, Carpenter PB (2012) Understanding the language of Lys 36 methylation at histone H3. Nat Rev Mol Cell Biol 13:115–126. https://doi.org/10.1038/nrm3274

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Li J, Duns G, Westers H, Sijmons R, van den Berg A, Kok K (2016) SETD2: an epigenetic modifier with tumor suppressor functionality. Oncotarget 7:50719–50734. https://doi.org/10.18632/oncotarget.9368

    Article  PubMed  PubMed Central  Google Scholar 

  108. Piva F et al (2015) BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: molecular diagnostics and possible targets for personalized therapies. Expert Rev Mol Diagn 15:1201–1210. https://doi.org/10.1586/14737159.2015.1068122

    Article  PubMed  CAS  Google Scholar 

  109. Parker H et al (2016) Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia 30:2179–2186. https://doi.org/10.1038/leu.2016.134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. McKinney M et al (2017) The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discov 7:369–379. https://doi.org/10.1158/2159-8290

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Chen Z, Raghoonundun C, Chen W, Zhang Y, Tang W, Fan X, Shi X (2018) SETD2 indicates favourable prognosis in gastric cancer and suppresses cancer cell proliferation, migration, and invasion. Biochem Biophys Res Commun 498:579–585. https://doi.org/10.1016/j.bbrc.2018.03.022

    Article  PubMed  CAS  Google Scholar 

  112. Liu L, Guo R, Zhang X, Liang Y, Kong F, Wang J, Xu Z (2017) Loss of SETD2, but not K3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients. Biosci Trends 11:214–220. https://doi.org/10.5582/bst.2016.01228

    Article  PubMed  CAS  Google Scholar 

  113. Martinelli G et al (2018) SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. Leukemia 32:139–148. https://doi.org/10.1038/leu.2017.183

    Article  PubMed  CAS  Google Scholar 

  114. Pfister SX et al (2015) WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28:557–568. https://doi.org/10.1016/j.ccell.2015.09.015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Chen K, Liu J, Liu S, Xia M, Zhang X, Han D, Jiang Y, Wang C, Cao X (2017) Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 170:492–506. https://doi.org/10.1016/j.cell.2017.06.042

    Article  PubMed  CAS  Google Scholar 

  116. Park IY, Chowdhury P, Tripathi DN, Powell RT, Dere R, Terzo EA, Rathmell WK, Walker CL (2016) Methylated α-tubulin antibodies recognize a new microtubule modification on mitotic microtubules. MAbs 8:1590–1597

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Park IY et al (2016) Dual chromatin and cytoskeletal remodeling by SETD2. Cell 166:950–962. https://doi.org/10.1016/j.cell.2016.07.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Georgoulis A, Vorgias CE, Chrousos GP, Rogakou EP (2017) Genome instability and γH2AX. Int J Mol Sci. https://doi.org/10.3390/ijms18091979 (Epub before print)

    Article  PubMed  PubMed Central  Google Scholar 

  119. Min A et al (2017) AZD6738, a novel inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol Cancer Ther 16:566–577. https://doi.org/10.1158/1535-7163.MCT-16-0378

    Article  PubMed  CAS  Google Scholar 

  120. Jossé R et al (2014) ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res 74:6968–6979. https://doi.org/10.1158/0008-5472.CAN-13-3369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Hocke S et al (2016) A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers. Oncotarget 7:7080–7095. https://doi.org/10.18632/oncotarget.6857

    Article  PubMed  PubMed Central  Google Scholar 

  122. Stucki M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP (2005) MDC1 directly binds phosphorylated H2AX to regulate cellular responses to DNA double-stranded breaks. Cell 123:1213–1226

    Article  PubMed  CAS  Google Scholar 

  123. Lee MS, Edwards RA, Thede GL, Glover JN (2005) Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail. J Biol Chem 280:32053–32056

    Article  PubMed  CAS  Google Scholar 

  124. Kleiner RE, Verma P, Molloy KR, Chait BT, Kapoor TM (2015) Chemical proteomics reveals gammaH2AX-53BP1 interaction in the DNA damage response. Nat Chem Biol 11:807–814. https://doi.org/10.1038/nchembio.1908

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Goldberg M, Stucki M, Falck J, D’Amours D, Rahman D, Pappin D, Bartek J, Jackson SP (2003) MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421:952–956

    Article  PubMed  CAS  Google Scholar 

  126. Stewart GS, Wang B, Bignell CR, Tylor AM, Elledge SJ (2003) MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421:961–966

    Article  PubMed  CAS  Google Scholar 

  127. Zhang J, Ma Z, Treszezamsky A, Powell SN (2005) MDC1 interacts with Rad51 and facilitates homologous recombination. Nat Struct Mol Biol 12:902–909

    Article  PubMed  CAS  Google Scholar 

  128. Melander F, Bekker-Jensen S, Falck J, Bartek J, Mailand N, Lukas J (2008) Phosphorylation of SDT repeats in the MDC1N terminus triggers retention of NBS1 at the DNA damage-modified chromatin. J Cell Biol 181:213–226. https://doi.org/10.1083/jcb.200708210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Sennoy TR et al (2017) CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair. Ann Oncol 28:1495–1507. https://doi.org/10.1093/annonc/mdx165

    Article  Google Scholar 

  130. Lottersberger F, Bothmer A, Robbiani DF, Nussenzweig MC, de Lange T (2013) Role of 53BP1 oligomerization in regulating double-stranded break repair. Proc Natl Acad Sci USA 110:2146–2151. https://doi.org/10.1073/pnas.1222617110

    Article  PubMed  Google Scholar 

  131. Somyajit K, Mishra A, Jameei A, Nagaraju G (2015) Enhanced non-homologous end joining contributes toward synthetic lethality of pathological RAD51C mutants with poly (ADP-ribose) polymerase. Carcinogenesis 36:13–24. https://doi.org/10.1093/carcin/bgu211

    Article  PubMed  CAS  Google Scholar 

  132. Gray HJ, Bell-McGuinn K, Fleming GF, Cristea M, Xiong H, Sullivan D, Luo Y, McKee MD, Munasinghe W, Martin LP (2018) Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies. Gynecol Oncol 148:507–514. https://doi.org/10.1016/j.ygyno.2017.12.029

    Article  PubMed  CAS  Google Scholar 

  133. Ledermann J et al (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852–861. https://doi.org/10.1016/S1470-2045(14)70228-1

    Article  PubMed  CAS  Google Scholar 

  134. Bhattacharjee S, Nandi S (2017) Synthetic lethality in DNA repair network: a novel avenue in targeted cancer therapy and combination therapeutics. IUBMB Life 69:929–937. https://doi.org/10.1002/iub.1696

    Article  PubMed  CAS  Google Scholar 

  135. Yuan SS, Lee SY, Chen G, Song M, Tomlinson GE, Lee EY (1999) BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 59:3547–3551

    PubMed  CAS  Google Scholar 

  136. Zhao W et al (2017) BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550:360–365. https://doi.org/10.1038/nature24060

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Xu G et al (2015) REV7 counteracts DNA double-stranded break resection and impacts PARP inhibition. Nature 521:541–544. https://doi.org/10.1038/nature14328

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Bhattacharjee S, Nandi S (2017) DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway. Cell Commun Signal 15:41. https://doi.org/10.1186/s12964-017-0195-9

    Article  PubMed  PubMed Central  Google Scholar 

  139. Yu AM, McVey M (2010) Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic Acids Res 38:5706–5717. https://doi.org/10.1093/nar/gkq379

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Kent T, Chandramouly G, McDevitt SM, Ozdemir AY, Pomerantz RT (2015) Mechanism of microhomology-mediated end-joining promoted by human RNA polymerase θ. Nat Struct Mol Biol 22:230–237. https://doi.org/10.1038/nsmb.2961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A (2015) Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 518:254–257. https://doi.org/10.1038/nature14157

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Ceccaldi R et al (2015) Homologous-recombination-deficient tumors are dependent on Polθ-mediated repair. Nature 518:258–262. https://doi.org/10.1038/nature14184

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Wyatt DW, Feng W, Conlin MP, Yousefzaden MJ, Roberts SA, Mieczkowski P, Wood RD, Gupta GP, Ramsden DA (2016) Essential roles of polymerase θ-mediated end joining in the repair of chromosome breaks. Mol Cell 63:662–673. https://doi.org/10.1016/j.molcel.2016.06.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Bhattacharjee S, Nandi S (2016) Choices have consequences: the nexus between DNA repair pathways and genomic instability in cancer. Clin Transl Med 5:45

    Article  PubMed  PubMed Central  Google Scholar 

  145. Mateos-Gomez PA, Kent T, Deng SK, McDevitt S, Kashkina E, Hoang TM, Pomerantz RT, Sfeir A (2017) The helicase domain of Polθ counteracts RPA to promote alt-NHEJ. Nat Struct Mol Biol 24:1116–1123. https://doi.org/10.1038/nsmb.3494

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Ray Chaudhuri A et al (2016) Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535:382–387. https://doi.org/10.1038/nature18325

    Article  PubMed  CAS  Google Scholar 

  147. Ding X et al (2016) Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. Nat Commun 7:12425. https://doi.org/10.1038/ncomms12425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Nicolae CM, Aho ER, Choe KN, Constantin D, Hu HJ, Lee D, Myung K, Moldovan GL (2015) A novel role for the mono-ADP-ribosyltransferase PARP14/ARTD8 in promoting homologous recombination and protecting against replication stress. Nucleic Acids Res 43:3143–3153. https://doi.org/10.1093/nar/gkv147

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Boulikas T (1990) Poly(ADP-ribosylated) histones in chromatin replication. J Biol Chem 265:14638–14647

    PubMed  CAS  Google Scholar 

  150. Davies H et al (2017) HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 23:517–525. https://doi.org/10.1038/nm.4292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S, Tominaga Y, Kohno T (2016) Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Discov 6:430–445. https://doi.org/10.1158/2159-8290

    Article  PubMed  CAS  Google Scholar 

  152. Ronnekleiv-Kelly SM, Sharma A, Ahuja N (2017) Epigenetic therapy and chemosensitization in solid malignancy. Cancer Ther Rev 55:200–208. https://doi.org/10.1016/j.ctrv.2017.03.008

    Article  CAS  Google Scholar 

  153. Hess-Stumpp H (2005) Histone deacetylase inhibitors and cancer: from cell biology to the clinic. Eur J Cell Biol 84:109–121

    Article  PubMed  CAS  Google Scholar 

  154. Marks PA, Xu WS (2009) Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem 107:600–608. https://doi.org/10.1002/jcb.22185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Conti C, Leo E, Eichler GS, Sordet O, Martin MM, Fan A, Aladjem MI, Pommier Y (2010) Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage. Cancer Res 70:4470–4480. https://doi.org/10.1158/0008-5472.CAN-09-3028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Seah KS, Loh JY, Nguyen TT, Tan HL, Hutchinson PE, Lim KK, Dymock BW, Long YC, Lee EJD, Shen HM et al (2018) SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling. Exp Cell Res. https://doi.org/10.1016/j.yexcr.2018.06.029

    Article  PubMed  Google Scholar 

  157. Wiegmans AP, Yap P, Ward A, Lim YC, Khanna KK (2015) Differences in expression of key DNA damage repair genes after epigenetic-induced BRCAness dictate synthetic lethality with PARP1 inhibition. Mol Cancer Ther 14:2321–2331. https://doi.org/10.1158/1535-7163.MCT-15-0374

    Article  PubMed  CAS  Google Scholar 

  158. Lord CJ, Ashworth A (2017) PARP inhibitors: synthetic lethality in the clinic. Science 355:1152–1158. https://doi.org/10.1126/science.aam7344

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I apologize to those authors whose work could not be cited due to space limitations. I thank Rebecca Jackson for editing a draft of this manuscript. This work was supported by a Singapore Ministry of Education Academic Research Fund (MOE2016-T2-2-063).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Ee Sin Chen

  2. National University Health System (NUHS), Singapore, 119228, Singapore

    Ee Sin Chen

  3. NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore

    Ee Sin Chen

  4. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore

    Ee Sin Chen

Authors
  1. Ee Sin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ee Sin Chen.

Ethics declarations

Conflict of interest

The author declares that he has no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, E.S. Targeting epigenetics using synthetic lethality in precision medicine. Cell. Mol. Life Sci. 75, 3381–3392 (2018). https://doi.org/10.1007/s00018-018-2866-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2866-0

Keywords

Search

Navigation