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Page 304 Ponnusamy et al. Cancer Drug Resist 2019;2:297-312 I http://dx.doi.org/10.20517/cdr.2018.11

Figure 2. Epigenetic deregulation mediates cellular reprogramming in acquired chemoresistance in breast cancer. Upon exposure to
chemotherapy, cancer cells which develop transient (drug tolerant phenotype) may further acquire cancer stem cell (CSC)-like features
characterized by enrichment for stem cell markers, slow-cycling and quiescence to facilitate higher levels of resistance development.
Similarly, cancer cells preferentially evoke EMT process to evade cytotoxicity. During EMT process, cells with epithelial phenotype
progressively loose epithelial markers and gain mesenchymal markers to become aggressive and invasive phenotype. EMT and CSC
cross-talk using same signaling pathways to establish acquired resistance. Epigenetic deregulation mediates the acquisition of both
EMT and stemness to induce chemoresistance, thus, potential epigenetic therapy targeting the cellular reprogramming could address
chemoresistance issues

Aberrant epigenetic changes associated with EMT/CSC-induced chemoresistance
The reversible nature of EMT and plasticity of CSCs are strategically structured by tight genetic-epigenetic
regulation to exert their functional role in chemoresistance . These transient changes are regulated through
[8]
various epigenetic signaling machineries including altered chromatin state and epigenetic modifications.
Functional role of DNA methylation and histone modification in establishing the CSC plasticity and
differentiation, and epigenetic marks that identifying embryonic as well as cancer stem cells have extensively
been reviewed [6,56,57] . Deregulation in the DNA methylation and chromatin landscape of both oncogenes
as well as tumor suppressors genes initiate the rise of CSCs and EMT. Chemotherapeutic drug-induced
DNA-hypermethylation impact the tumor cells response to the cytotoxicity. Concurrently, upon exposure
to drug, tumor cells undergo cellular reprogramming to acquire survival-associated phenotypical changes
such as EMT and stemness. In addition to key epigenetic events, metabolic components have recently been
implicated in altering the plasticity, physiological state and fate of the stem cells. Epigenetic metabolic donors/
factors such as S-adenosyl methionine (SAM), acetyl-CoA, flavin adenine dinucleotide (FAD), nicotinamide
adenine nucleotide (NAD+) and α-ketoglutarate influence the DNA methylation and histone modifications
to guide the normal and cancer cells towards CSC-like transition . These concurrent deregulations that
[58]
lead to chemoresistance support the likely impact of epigenetic fluctuations in EMT-CSC transduction
pathway [Figure 2].

Mounting evidence emphasizes the role of epigenetic deregulation on several genes and pathways that
linked with EMT, cancer stemness and acquired resistance. Besides regulation of EMT-CSC genes, aberrant
methylation (hypo/hyper) and histone modifications are found to regulate MDR1, MRP2, MRP5, BCRP,
Catalase, ALDH1, ESR1, ID4, PITX2, Cyclin D2, P16, P53, Survivin, Bcl2, HIF1α, Leptin, Stromal cell-derived
factor receptor 1, MLH1 and MSH2 genes which may provide survival advantage to cytotoxicity [53,59-61] . These
genes work through distinct mechanisms to provide mechanism-specific drug tolerance, however, may also