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]