Epitranscriptomics and epiproteomics in cancer drug resistance: therapeutic implications

Abstract

Drug resistance is a major hurdle in cancer treatment and a key cause of poor prognosis. Epitranscriptomics and epiproteomics are crucial in cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, epitranscriptomic and epiproteomic modification has been investigated on their roles in overcoming drug resistance. In this review article, we summarized the recent progress in overcoming cancer drug resistance in three novel aspects: (i) mRNA modification, which includes alternative splicing, A-to-I modification and mRNA methylation; (ii) noncoding RNAs modification, which involves miRNAs, lncRNAs, and circRNAs; and (iii) posttranslational modification on molecules encompasses drug inactivation/efflux, drug target modifications, DNA damage repair, cell death resistance, EMT, and metastasis. In addition, we discussed the therapeutic implications of targeting some classical chemotherapeutic drugs such as cisplatin, 5-fluorouridine, and gefitinib via these modifications. Taken together, this review highlights the importance of epitranscriptomic and epiproteomic modification in cancer drug resistance and provides new insights on potential therapeutic targets to reverse cancer drug resistance.

Fig. 1

mRNA modification in cancer drug resistance. a Schematic representation of examples of alternative splicing patterns causing cancer drug resistance, including skipping of one exon, skipping of multiple exons, mutually exclusive exons, and exon inclusion. b Schematic representation of A-to-I RNA editing mediated drug-resistance-related functional consequences including structure modification of targeted protein, target escape from silencing of miRNA, off-target effects of miRNA, pre-miRNA degradation, aberrant splicing of targeted mRNA. c Schematic representation of m⁶A modification network in targeted genes causing cancer drug resistance. In the nucleus, m⁶A is deposited in nascent pre-mRNA by a “writer” multiprotein complex (i.e., METTL3, METTL14, and other related protein) and removed by “eraser” demethylases (i.e., FTO and ALKBH5). In the cytoplasm, the m⁶A modifications are recognized by “reader” proteins, resulting in stabilization or decay or enhanced translation. Specific examples of each mRNA modification event discussed in the text are shown

Fig. 2

The functions of noncoding RNAs in cancer drug resistance. LncRNA can directly interact with target genes, or act as ceRNA to interact with miRNA to participate in gene expressions; circRNAs can act as “miRNA sponge” to release the inhibitory effect of miRNA on its target genes. The noncoding RNAs could be potential targets of drug resistance in cancers due to their functions in cell proliferation, metastasis, and EMT

Fig. 3

An illustration of the process of autophagy and the roles of lncRNAs in drug resistance via autophagy. The cells engulf and encapsulate cytoplasmic proteins or organelles into vesicles, and then vesicles fuse with lysosomes to form autophagy lysosomes, subsequently, autophagy lysosomes degrade the contents, recycle amino acids, fatty acids, and nucleotides. LncRNA MALAT1, and SNHG family could facilitate drug resistance via inducing autophagy and activating expressions of autophagy-related proteins

Fig. 4

The PTM status of human proteins. All data is retrieved from Uniprot database and updated as of 2015-05. The number of proteins with different types of PTMs are illustrated in the barplot (left); the percentages of amino acids modified in each type of PTMs are illustrated in the circle plots (right)

Fig. 5

The mechanisms of PTMs in cancer cell chemoresistance. a The inactivation of Capecitabine through the regulation of CES, CDA, TYMP, and DPD enzymes. b The drug efflux process mediated by ABC transporter proteins and the modifications of these transporters. c The modification of ERBB receptors through mutations and PTMs resulting in multiple drug resistance. d DNA damage repair system in cancer cells could also result in drug resistance, and this process is mediated through the repression of ATM and ATR, as well as p53 proteins, and induction of specialized DNA polymerases, such as Poly beta, kappa and zeta. e The repression of apoptosis in cancer cells, which is mainly achieved through the inhibition of p53 via either mutation or PTMs. The overexpression of MCL-1/BCL-2 and repression of BAX/BAK proteins also contribute to this process. f The repression of autophagy in cancer cells. MTORC1 is triggered through PI3K-AKT pathways, which further inhibits the phosphorylation of ULK1, and impedes the autophagy process. g The activation of EMT in cancer cells. EMT process is triggered through multiple signaling pathways including TGFβR and WntR, which activate SNAIL and TWIST transcription factors. These EMT-TFs repress the expression of E-cadherin and promote the expression of N-cadherin, vimentin, and fibronectin, which further promote EMT process

Fig. 6

Epitranscriptomic and epiproteomic modifications could be the potential therapeutic targets in cancers. The critical genes and proteins in both modifications could reverse the resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouridine, EGFR-TKI, and cisplatin