Table 4.
Epigenetic alterations downstream of p53.
| Gene | Gene Name | Gene Function | Epigenetic Event | Reference |
|---|---|---|---|---|
| HRK | BCL-2-interacting protein | Proapoptotic p53 target protein, whose expression is reversible by methylation inhibitors (5-aza-deoxycytidine) and further enhanced by histone deacetylase inhibitors (trichostatin A, depsipeptide) | HRK promoter methylation significantly correlated with wildtype p53 in 58 CRC. | Obata et al., 2003 [89] |
| XEDAR | X-linked ectodermal dysplasia receptor | XEDAR is a member of the tumor necrosis factor receptor family. P53 upregulates XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. Inactivation of XEDAR results in enhanced cell adhesion and spreading, and resistance to p53-induced apoptosis. | XEDAR downregulation by hypermethylation or TP53 mutations in CRC cell lines and biopsies | Tanikawa et al., 2009 [90] |
| IGFBP7 | Insulin-like growth factor-binding protein 7 | P53 induces expression of IGFBP7 upon binding to a p53 response element in intron 1 of IGFBP7. | IGFBP7 methylation was significantly higher in 83 CRC biopsies than in normal colonic tissue. 5-Aza-2′-deoxycytidine restored p53-induced IGFBP7 expression. IGFBP7 methylation significantly correlated with wildtype p53. | Suzuki et al., 2010 [91] |
| DLC1 | Deleted in liver cancer 1 | Tumor suppressor. The functional DLC1-i4 promoter is activated by wild-type p53. | DLC1 isoform 4 (DLC1-i4) was methylated in 2/4 CRC cell lines (=50%). Demethylation with 5-aza-2′-deoxycytidine restored DLC-i4 expression. | Low et al., 2011 [92] |
| G9a/KMT1C/EHMT2 | Lysine methyltransferase 1C, euchromatic histone methyltransferase 2 | Histone methyltransferase that catalyzes mono- and dimethylation of histone H3K9 | G9a dimethylated p53 at lysine 373. This transactivated PLK1 expression and increased proliferation | Zhang et al., 2018 [93] |
| miR-34b/c | Micro-RNA 34b/c | p53 activates the transcription of miR-34 family members. The miR-34b/c CpG island is a bidirectional promoter, regulating the expression of both miR-34b/c and B-cell translocation gene 4 (BTG4). Methylation of this promoter silenced BTG4 transcription. | miR-34b/c CpG island methylation in 100/111 (=90%) CRC | Toyota et al., 2008; Navarro and Lieberman, 2015 [98,99] |