EEpigenetics is a branch of genetics that studies the heritable changes of gene expression without changing the nucleotide sequence of genes. It is strictly regulated by a variety of chemical modifying enzymes and recognition proteins, which are often
called “writers”, “erasers”, and “readers”.411,412 The writers refer to
enzymes that transfer chemical groups to DNA or histones, which
include DNA methyltransferases (DNMTs), histone acetyltransferases
(HATs), and histone lysine methyltransferases (KMTs). The
erasers remove post-translational modifications, and include
histone deacetylases (HDACs) and histone lysine demethylases
(KDMs). The readers are proteins that can recognize the modified
histones or DNA, such as methyl-binding domain proteins, and
bromodomain and extra-terminal (BET) family proteins (Fig. 3).
Abnormal epigenetic regulation is also closely related to various
diseases including tumor, immune diseases, and many rare
diseases. Though numerous epigenetic regulatory proteins have
been identified as potential disease targets, only fewer epigenetic
drugs are approved for clinical use at present.
EZH2 Inhibitors
Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, functions as a catalytic subunit of the polycomb repressor complex 2 (PRC2), which also comprises other members including embryonic
ectoderm development (EED), suppressor of zeste 12 (SUZ12), and histone-binding proteins RbAp46/48.413 PRC2 is one of the two core complexes of polycomb group proteins (PcGs), and is responsible
for transferring methyl groups from S-adenosyl-L-methionine (SAM)
to lysine 27 on histone H3 (H3K27) through its C-terminal SET
domain, resulting in chromatin compaction and transcriptional
silencing of target genes. As the central component of PRC2, EZH2
is involved in numerous epigenetic modifications that are
associated with cell proliferation, differentiation, survival, adhesion,
and DNA damage repair. Dysfunction of EZH2 is closely related
to tumorigenesis and progression. Accumulating evidence has
confirmed that EZH2 is frequently mutated and abnormally
overexpressed in various malignant tumors including prostate
cancer,415,416 ovarian cancer,417 endometrial carcinoma,418 breast
cancer,419 melanoma as well as hematological malignancies,420
such as NHL, B-cell lymphoma, and T-cell ALL.421–424 It promotes
tumorigenesis mainly through three mechanisms: PRC2-dependent
H3K27 methylation, PRC2-dependent non-histone protein methylation,
and PRC2-independent coactivator of transcriptional factors.
Given the evidence for EZH2 enzymatic gain of function being a
cancer driver, inhibition of EZH2 has been thought of as a novel and
promising approach for cancer therapy.
