The Impact of Mutant p53 in the Non-Coding RNA World

Abstract

Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.Biomolecules 2020, 10, 472 2 of 15 heterotetrameric mut-p53/wt-p53 complex can inhibit the function of the remaining wt-p53 in tumor suppression [8,9]. Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).

A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

“…Mutant p53 in conjunction with the YAP/TEAD transcription-competent complex is involved in an upregulation of a circular form of oncogenic PVT1 [253]. The currently known interrelations of mutant p53 with several oncogenic ncRNAs are representative examples of a still limited but rapidly expanding knowledge of the interplay of the main driver oncoproteins with ncRNAs [254]. This knowledge will surely grow significantly in the nearby future as over 30 thousand lncRNAs alone are found in a typical human transcriptome.…”

“…Noticing that broader mechanisms of ncRNA deregulation in cancer are crossing over to other targetable oncogenic pathways could help in making the ncRNA targeting more robust. For example, the mentioned CMYC or mutant p53 effects on the activity and maturation of wide miRNA populations [252,254] can be theoretically co-targeted along with selected oncomiRs.…”

Gain-of-function mutant p53 in cancer progression and therapy

“…Mutp53 interacts with many different proteins other than transcription factors, including tumor suppressors and oncogenic proteins, to affect their functions. Additionally, mutp53 regulates expression of many noncoding RNAs, including microRNAs (miRNAs), circular RNAs (circRNAs), and long noncoding RNAs (lncRNA), to exert its GOF activities ( Liu et al., 2017a ; Di Agostino, 2020 ). In this review, we summarize recent advances in studies on mutp53 GOF in cancer and mutp53-targeted cancer therapies.…”

Novel insights into the mechanisms by which lncRNAHOTAIR regulates migration and invasion in HeLa cells

“…It is thus of great interest that we show that the role of YAP1 as an upstream transcriptional regulator of RPL23, at least in part, are mediated by the regulation of RPL23 expression in HeLa cells. The p53 mutation, which loses tumor suppressive functions and gains tumor-promoting activities (79), was reported to be associated with aggressive growth and increased recurrence rates for certain tumors (80). Here, we showed that RPL23 increased the expression of mutant p53 in HeLa cells.…”