Fig. 2

Therapeutic resistance involvement in epigenetic modifications and EMT/MET. a Schematic representation of therapy-induced drug resistance through chemical epigenetic modifications. Four core histone proteins (H2A, H2B, H3, and H4) can be diversely modified by multiple enzymes that result in methylation, acetylation, phosphorylation, or ubiquitylation. DNA can be methylated at the 5-carbon of the cytosine base to form 5-methylcytosine (5-mC), which can be further oxidized to form 5-hydroxymethyl cytosine (5-hmC). Enzymes involved in the epigenetic modifications of either histone or DNA can be utilized as potential future therapeutic targets against tumor cell plasticity. K, Lysine; S, Serine; R, Arginine; T, Threonine; me, methylation; ac, acetylation; ub, ubiquitination; P, phosphorylation; HAT, histone acetyltransferase; HMT, histone methyltransferase; HDAC, histone deacetylase; HDM, histone demethylase; TRIM, tripartite mortif; MSK1, mitogen- and stress-activated protein kinase 1; DNMT, DNA methyltransferase; TET, ten-eleven translocation enzymes. b Primary tumor cells undergo EMT and MET to achieve metastasis. Primary tumor cells undergo EMT by losing epithelial traits and acquiring mesenchymal characteristics, which enables tumor cells to migrate and invade into blood or lymphatic vessels. In circulation, tumor cells exhibit a “partial EMT” within the epithelial-mesenchymal spectrum. During colonization, migratory tumor cells with mesenchymal traits undergo MET to restore epithelial characteristics and proliferate to form a secondary tumor. Therapeutic resistance and invasiveness are higher in mesenchymal states, whereas a hybrid state of epithelial and mesenchymal indicates the highest level of stemness and capacity of self-adaptation. The process of EMT/MET is regulated by crosstalk among genomic factors, MET-TFs, and multiple signaling pathways. EM, epithelial-mesenchymal transition, MET mesenchymal-epithelial transition, TF transcription factor, miR microRNA