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Ponnusamy et al. Cancer Drug Resist 2019;2:297-312 I http://dx.doi.org/10.20517/cdr.2018.11 Page 303

In concert with DNA methylation and histone modifications, chromatin remodeling complex proteins
involve in epigenetic regulation. Among various drivers of chromatin remodeling as reported earlier [46-48] ,
the SWI/SNF complex, nucleosome remodeling factor (NuRF), Mi‐2/NuRD (nucleosome remodeling and
deacetylase) complex and Polycomb repressor complex (PRCs) are well known to be involved in cellular
reprogramming. PRCs directly methylate DNA and methylate histones through HMT named Enhancer
of Zeste Homologue 2 (EZH2) to exert their repressive function [49,50] . Particularly, BMI-1 containing PRC1
and EZH2/ SUV12 (suppressor of Zeste homolog 12) containing PRC2 complexes are known to involve in
chemoresistance [46-48] .

Co-ordination between DNA methylation, histone modifications and chromatin remodeling
With the growing number of studies, the understanding of dynamic epigenetic regulation is also growing, but
still it is unclear how the epigenetic events unfold, i.e., whether DNA sequence- associated DNA methylation
signals the histone modifications or chromatin-guided initiation serve as signal for DNA methylation
process to begin. Nevertheless, it is well established that the epigenetic layers such as DNA methylation and
histone modifications cross-talk to exert their effect in a tightly regulated fashion at global and loci-specific
levels [44,45,51] . DNMTs-induced CpG methylation engage the methyl-CpG-binding machinery proteins
(MeCPs, MBDs, UHRFs) bind to the methylated CpG sites. This complex collaborates with catalytically
active deacetylases (Sin3 and HDACs) and HMTs which sequentially are recruited to methylated promoter
to impose another epigenetic layer that enact histone deacetylation and methylation [44,45,51] . HMTs including
SUV39H1 and PRMT5 influence the recruitment and stability of DNMTs. It is evident from recent
understandings that histones acetylation protects against DNA methylation through insulators (boundary
elements). These insulator components in the genes recruit HATs to keep the chromatin relaxed to permit
TFs while limiting the DNMTs and sequential binding of MBD protein and Mi-2 deacetylase complex [45,51] .

Aberrant epigenetic changes contribute to acquired chemoresistance
While DNA methylation and histone modifications orchestrate various essential normal cellular physiology,
aberration in the epigenetic landscape also contribute to tumorigenesis and resistance development [8,23,52] .
In vitro, in vivo and clinical studies, clearly supported that epigenetic aberration mediated through global
hypomethylation coupled with localized promoter hyper-methylation and post-translational histone
modifications underwrite chemoresistance [23,53] .

Aberrant DNA methylation events occur at early stages of tumor development and trigger further genetic/
epigenetic changes to contribute to carcinogenesis and resistance induction. Overexpression of DNMTs,
elevated percentage of 5-methyl cytosine content and associated hyper-methylation-mediated repressed gene
expression, loss of global DNA methylation and associated transcriptional activation have been reported in
breast cancer [23,53,54] . Likewise, aberrant HDAC1, HAT1, p300 and Suv4-20h2 HMT expression and associated
alterations in genome-wide histone modification on H3 and H4 including atypical acetylation (of H3K9,
H3K18, H3K56, H4K12 and H4K16), phosphorylation (of H3 serine 10) and methylation (of H3K9 and
H4K20) have been reported to occur in naive breast cancer indicating poor prognosis, upon treatment with
DNA damaging cytotoxic drugs and chemoresistance [53,55] .

Reversible transcriptional changes controlled by the dynamic epigenetic changes causing heterogeneity in
a tumor cell population which may serve as a non-genetic source of variation leading to enrichment of
chemoresistant cells. Epigenetic deregulation-mediated pathways include several key signaling pathways
involving growth/proliferation signaling, microenvironment, EMT-CSC, apoptosis, drug transport,
metabolism, DNA damage repair and others . With this review focusing on cellular reprogramming, scope
[23]
of further discussion narrowed down to how the EMT- CSC pathways induce chemoresistance through
epigenetic deregulation.