The Regulation of p53 by Ubiquitination and Implications for Therapeutic Targeting in Colorectal Cancer

<b>Background:</b> The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene <i>TP53</i> encoding for p53, which interferes with its normal function. <b>Methods:</b> The genomic series of colorectal cancer from the Cancer Genome Atlas (TCGA) was interrogated to discover genomic alterations and determine the mRNA expression of enzymes affecting p53 ubiquitination in colorectal cancers with wild-type and mutant <i>TP53</i>. <b>Results:</b> Genomic alterations of p53-regulating E3 ubiquitin ligases were uncommon in colorectal cancers, the most frequent being mutations in <i>RCHY1</i>. Several p53-regulating E3 ligases were well expressed in subsets of colorectal cancers, two of which, MDM2 and TRIM24, displayed higher mRNA expressions than the normal colorectal epithelia. The former was particularly upregulated in <i>TP53</i> wild-type colorectal cancers, and the latter was upregulated in both wild-type and mutant <i>TP53</i> cancers. Upregulation of TRIM24 in <i>TP53</i> mutant cancers was observed independently of the type of mutations (gain-of-function or other). Among E3 ligases used in proteolysis-targeting chimeras (PROTACs), VHL was upregulated together with its E2-conjugating enzyme UBE2S in colorectal cancers. <b>Conclusions:</b> This survey of p53-targeting ubiquitin ligases provides a roadmap for potential therapeutic strategies working by promoting the destruction of the mutant protein or reactivating its normal function in <i>TP53</i>-mutated colorectal cancers and promoting p53 function by preventing degradation in <i>TP53</i> wild-type cancers.