Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

SIMPLE SUMMARY: The tumor suppressor TAp73 is a member of the p53 family, which is inhibited in many human solid and hematological tumors. In contrast to those in the p53 gene, mutations in the p73 gene are very rare in tumors, suggesting that the decrease in TAp73 activity and expression detected in those tumors are caused mainly by coordinated post-translational modifications of TAp73. Thus, understanding and investigating these post-translational modifications will allow for the identification of new targets to overcome the downregulation of TAp73 and, ultimately, the development of novel cancer therapeutics. This review highlights the multiple post-translational modifications underlying TAp73 regulation in cancer cells and the growing importance of targeting their trigger enzymes as a promising antitumor strategy. ABSTRACT: The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.