Table 4.
Epigenetic modification of ferroptosis by methylation in cancer
| Cancer | Modification | Targets | Enzyme | Biological functions | Ref |
|---|---|---|---|---|---|
| GC | Methylation | ELOVL5 and FADS1 | - | The expression of elongation of ELOVL5 and FADS1 is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. | 190 |
| CRC | Methylation | SLC2A1 | - | Increased methylation levels of SLC2A1 were greatly, inhibited autophagy and ferroptosisis correlated with the immunosuppression, resulting in a poor prognosis for patients. | 191 |
| HCC | Methylation | PCDHB14 | - | PCDHB14 is inactivated by aberrant methylation of its promoter in HCC patients and that PCDHB14 functions as a tumor suppressor to promote cell cycle arrest, inhibit cell proliferation, and induce ferroptosis. PCDHB14, a novel gene induced by p53 activation, significantly enhances RNF182-mediated degradation of p65 to inhibit HCC progression and promote cell sensitivity to ferroptosis by suppressing SLC7A11. | 129 |
| NSCLC | Methylation | GPX4 | - | Upstream of GPX4 there was low DNA methylation sites and enhanced level of H3K4me3 and H3K27ac lead to increase GPX4. Inhibition of tumor GPX4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. | 192 |
| NSCLC | Methylation | GPX4 | EP300 | Knockdown of CREB inhibited cell viability and growth by promoting ferroptosis. CREB suppressed ferroptosis by binding the promoter region of GPX4, and this binding could be enhanced by EP300. | 193 |
| ccRCC | Methylation | β-OHB | - | CX3CL1 overexpression inhibited tumor cell proliferation and metastasis and promoted tumor ferroptosis sensitivity in ccRCC.The expression of CX3CL1 in ccRCC is correlated with its DNA methylation level. | 195 |
| ccRCC | Methylation | SDH | - | Increased methylation and high SDH promoter mutation rates lead to deficiency of SDH, thereby promoting tumorigenesis through weakening of ferroptosis. | 196 |
| ALL | Methylation | FSP1 | - | The promoter of the gene coding for FSP1 is hypermethylated in ALL, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression promotes ALL-tumor growth. | 197 |
| MM | Methylation | ND | - | Ferroptosis induction leads to DNA methylation and histone modification changes associated with cellular senescence | 198 |
| Fibrosarcoma | Methylation | SLC7A11 | KDM3B | Histone demethylase KDM3B results in decreased histone H3 lysine 9 methylation and protects against ferroptosis by upregulating SLC7A11 through cooperation with the transcription factor ATF4. | 199 |
| Osteosarcoma | Methylation | SLC7A11 | KDM4A | Upregulated KDM4A was associated with poorer prognosis. KDM4A knockdown promoted ferroptosis through regulating SLC7A11 transcription by controlling H3K9me3 demethylation in the promoter region of SLC7A11. | 200 |
ALL acute lymphoblastic leukemia, CREB cAMP response element-binding protein, CYP2E1 cytochrome P450 family two subfamily E member 1, ELOVL5 elongation of very long-chain fatty acid protein 5, EP300 E1A binding protein P300, FADS1 fatty acid desaturase 1, FSP1 ferroptosis suppressor protein 1, HMGCL ketogenesis-related hydroxy-methyl-glutaryl-CoA lyase, KDM3B histone lysine demethylase 3B, KDM4A histone lysine demethylase 4A, β-OHB β-hydroxy-butyric acid, NAT10 N-acetyltransferase 10, MM multiple myeloma, SDH succinate dehydrogenase