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Targeting epigenetics using synthetic lethality in precision medicine

Review

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.

Keywords

Synthetic lethality Epigenetics Precision medicine Cancers Gene network 

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

Notes

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).

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Biochemistry, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.National University Health System (NUHS)SingaporeSingapore
  3. 3.NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences InstituteNational University of SingaporeSingaporeSingapore
  4. 4.NUS Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore

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