Table 1.
Epigenetic alterations upstream of p53.
| Gene | Gene Name | Gene Function | Epigenetic Event | Reference |
|---|---|---|---|---|
| UCHL1 | ubiquitin carboxyl-terminal hydrolase L1 | Tumor suppressor. Carboxyl-terminal ubiquitin hydrolase regulating cellular ubiquitin levels | UCHL1 methylation in 22/31 CRC (=71%). UCHL1 binds to and stabilizes p53 by the ubiquitination pathway, UCHL1 demethylation caused growth inhibition, G2/M arrest and induction of apoptosis. | Yu et al., 2008 [35] |
| BCL6B | B-Cell CLL/Lymphoma 6 Member B | Tumor suppressor. BCL6B activates p53 signaling and induces apoptosis. | BCL6B was methylated in 81/102 CRC (=79%). | Hu et al., 2015 [36] |
| RASSF10 | Ras-association domain family member 10 | RASSF10 activates p53 signaling and sensitizes to docetaxel. RASSF10 demethylation induced apoptosis and inhibited proliferation. | RASSF10 was methylated in 54/89 CRC (=61%) and was positively associated with tumor stage and metastasis. | Jin et al., 2015 [37] |
| HPSE2 | Heparanase 2 | Tumor suppressor. HPSE2 regulates p53 signaling and G1 cell cycle arrest. | HPSE2 hypermethylation correlated with shorter survival times of CRC patients. | Zhang et al., 2021 [38] |
| BMI1 | B Lymphoma Mo-MLV insertion region 1 homologue | Proto-oncogene. BMI1 is an epigenetic repressor by chromatin remodeling. p14ARF is silenced by BMI1. | p14ARF and wild-type p53 were upregulated in BMI1-mutant CRC. p14ARF is required for the induction of p53 and apoptosis. | Maynard et al., 2014 [39] |
| CDKN2A | Cyclin-dependent kinase inhibitor 2A | CDKN2A/p14ARF antagonizes MDM2-dependent p53 degradation. | p14ARF hypermethylation was increased in tumors with wildtype compared to mutated p53 without statistical significance. | Esteller et al., 2000 [40] |
| p14ARF promoter demethylation was associated with nuclear MDM2 expression (active state), p14ARF promoter hypermethylation with cytosolic MDM2 expression (inactive state). | Nuclear MDM2 expression was associated with p14ARF promoter demethylation in 33 CRC. | Esteller et al., 2001b [41] | ||
| Tumor suppressor. Regulates p53 protein stability by interaction with MDM2. p14ARF promoter hypermethylation abrogates wild-type p53 activity. | CDKN2A promoter hypermethylation was significantly correlated with restricted p53 overexpression and MDM2 overexpression. Epigenetic silencing of CDKN2A is a deregulating mechanism of the p53-MDM2-p14ARF pathway in CRC exhibiting restricted p53 overexpression. | Nyiraneza et al., 2012 [42] | ||
| APC | Adenomatous Polyposis Coli Protein | APC inhibits β-catenin, and β-catenin overexpression increases the TP53 mutation rate. | APC hypermethylation was associated with p53 mutation in 208 CRC. | Suehiro et al., 2008; Stamos and Weis, 2013 [43,44] |
| MGMT | O6-methylguanine-DNA methyltransferase | MGMT downregulation by promoter hypermethylation predisposes to p53 mutations. MGMT hypermethylation is associated with G > A mutations in TP53. | MGMT promoter hypermethylation was significantly correlated to G:C > A:T transition p53 mutations in 314 CRC. | Esteller et al., 2001a [45] |
| MGMT methylation was associated with G > A mutations in the TP53 gene. | Deng et al., 2008 [46] | |||
| No association between MGMT methylation and TP53 mutations in 261 CRC biopsies from Afro-American patients | Alonso et al., 2015 [47] | |||
| PTX3 | Pentraxin 3 | Tumor suppressor. PTX3 deficiency increases susceptibility to carcinogenesis by increasing DNA damage, p53 mutations, and inactivation of p53 downstream signaling (Mdm2, Bax, and Cdkn1a /p21). | Increasing PTX3 promoter methylation from normal colon epithelium to adenomas and CRC. | Bonavita et al., 2015 [48] |
| PCAF | P300/CBP-associated factor | Trimethylated histone H3K27 binding in the PCAF promoter attenuated its transcription. | Decreased PCAF impairs the acetylation of p53 and attenuates the p53-dependent transcription of p21, which results in the increased cyclin D1 expression and Retinobla-stoma 1 phosphorylation as well as increased resistance to 5-fluorouracil. | Liu et al., 2019 [49] |
| LACTB | Lactamase β | Tumor suppressor. LACTB binds to the p53 C terminus to inhibit p53 degradation by MDM2. | LACTB was significantly downregulated in CRC due to promoter methylation and histone deacetylation. | Zeng et al., 2018 [50] |
| TRIM67 | Tripartite motif containing 67 | Tumor suppressor. Upon stress, p53 binds to TRIM67 promoter and upregulates TRIM67 expression in a TRIM67/p53 self-amplifying loop. TRIMP67 interacts with the p53 C-terminus to inhibit p53 degradation by MDM2. | 108/138 CRC (=79%) downregulated TRIMP67 expression due to promoter methylation. Demethylation by treatment with 5-aza-2′-deoxycytidine restored TRIM67 expression in CRC cells. | Wang et al., 2019 [51] |
| COX2 | Cyclooxygenase 2 | Role in CRC progression. Converts arachidonic acid to prostaglandins | Methylation in 12/93 (=13%) CRC and 7/50 (=14%) colorectal ademonas. COX2 methylation was inversely related to p53 mutations. Functional relationship unclear | Toyota et al., 2000a [52] |
| CIMP | CpG island methylator phenotype | High levels of DNA methylation may predispose to carcinogenesis. | TP53 mutations in 10/41 (=24%) CIMP-positive CRC compared to 30/46 (=60%) CIMP-negative cases. Functional relationship unclear | Toyota et al., 2000b [53] |
| CIMP | CpG island methylator phenotype | CIMP correlated with wildtype p53. Functional relationship unclear | Konishi et al., 2007 [54] | |
| miR-34a | Micro-RNA 34a | miR-34a acts as translational repressor. | miR-34a activates p53 by inhibiting its acetylation by MTA2 and HDAC1. | Kaller et al., 2011 [55] |
| miR-34a methylation correlates with wild-type p53 in CRC and other tumor types. | Vogt et al., 2011 [56] |