RNA methylation and cellular response to oxidative stress-promoting anticancer agents

Figures & data

Figure 1. Schematic representation of the most common and best studied methyl-based modifications of the various classes of RNA, along with their main human methylases (“writers”), demethylases (“erasers”) and “readers”, which drive cellular responses when methylated ribonucleotides are detected. ALKBHs, AlkB Homolog 1, histone H2A dioxygenase; ALYREF, Aly/REF export factor; CMTR1–2, Cap methyltransferases 1 and 2; DNMT, DNA methyltransferases; FBL, fibrillarin; FTO, Fat mass and obesity-associated protein; FTSJ1–2, FtsJ RNA 2’-O-methyltransferases 1 and 2; HENMT1, HEN methyltransferase 1; IGF2BPs, insulin-like growth factor 2 mRNA binding proteins; METTLs, methyltransferase complex subunits; MRM1–3, mitochondrial rRNA methyltransferases 1–3; NML, nucleomethylin; NSUN, NOP2/Sun RNA methyltransferases; PCIF1, phosphorylated CTD interacting factor 1; RNMT, RNA guanine-7 methyltransferase; TRMT, tRNA methyltransferase; WTAP, Wilms tumor 1-associating protein; YBX1, Y-Box Binding Protein 1; YTHDCs, YTH Domain Containing proteins; YTHDFs, YTH N6-methyladenosine RNA binding proteins; ZCCHC4, zinc finger CCHC-type containing 4.

Table 1. RNA methylation and cancer resistance traits potentially related to redox rewiring.

Cancer	RNA methylation-related aspect	Anticancer agent	Resistance	Ref.
Pancreas	METTL3 LoF	5-FU	Increased	193
Colon	Increased mAs in p53 pre-mRNA	5-FU	Increased	195
Colon	METTL3-dependent methylation of LBX2-AS1 mRNA	5-FU	Increased	198
Colon	METTL3-dependent methylation of miR‑181d‑5p	5-FU	Increased	199
Breas	Hypermethylated 5′-UTR of miR-149	DOXO	Increased	204
Colon	METTL3-dependent A methylation in p53 mRNA	DOXO	Increased	195
Breast	METTL3-dependent hypermethylation of miR-221-3p	DOXO	Increased	209
Pancreas	METTL3 knockdown	Pt	Reduced	193
Esophagus	NSUN2-mediated hypermethylation of lncRNA	Pt	Increased	215
Lung	METTL3-dependent increase in m^6As in YAP pre-mRNA	Pt	Increased	216
Colon	METTL3-induced m^6A over-methylation of CBX8 mRNA	Pt	Increased	219
Testis	METTL3-induced m6A over-methylation of TFAP2C mRNA	Pt	Increased	221
Lung	miR-4443-dependent inhibition of METTL3	Pt	Increased	223
Leukemia	Hypermethylated cytosines	5-AZA	Increased	229
Ovary	m^6A modifications in FZD10 mRNA	PARPi	Increased	233
Lung	High levels of METTL3 mRNA	TKIs	Increased	237
Liver	Downregulation of METTL3-dependent methylation of As in 3′‐UTR of FOXO3 mRNA	TKIs	Increased	239
Lung	METTL3-mediated regulation of autophagy	TKIs	Increased	244
Lung	FTO-dependent downregulation of m^6A in myc mRNA	TKIs	Reduced	245
Liver	METTL3-induced adenosine hypermethylation of lncRNA NIFK-AS1	TKIs	Increased	249
Breast	METTL3-dependent hypermethylation of adenosines in 5′-UTR of AK4 mRNA	TMX	Increased	176
Breast	Downregulation of m^6A in 5′-UTR of ATF3 mRNA	TMX	Increased	256

Note: Abbreviations: 5-AZA, 5-azacytidine; 5-FU, 5-fluorouracil; 5′-UTR, 5′ untranslated region; DOXO, doxorubicin; LoF, loss of function; mAs, methylated adenosines; Pt, platinum-based compound; TKIs, tyrosine kinase inhibitors; TMX, tamoxifen. For abbreviations not listed here and for details on the specific redox relevance of the molecular targets indicated, see the text.

Figure 2. Schematic representation of the possible directions that future research activities and efforts may take to reveal in detail the role of the methylepitranscriptome in affecting or determining cancer cell response to treatments, also in terms of potential participation of redox-sensitive and redox-dependent biomolecular mechanisms.