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.
Highlights
Mature micro RNAs (miRNAs) are short, single-stranded non-coding RNAs (ncRNAs) of about 21–25 nucleotides in length whose main function is to regulate the levels of other RNAs, most frequently by binding them in a specific complementary sequence to the 3’ untranslated regions (3’-UTR) in the RNA targets inhibiting their use by either degradation or translational repression. miRNAs can bind coding regions, 5 -UTR, and open reading frames (ORF) regulating in this way the protein translation
As GOF TP53 mutations are associated with tumors under high replicative stress, high genomic instability, and reduced patient survival, it was very recently reported that mut-p53, by the induction of miR-205-5p expression, is able to repress the expression of genes involved in DNA repair of DNA double-strand breaks in head and neck squamous cell carcinoma (HNSCC) (BRCA1 and RAD17) [49]
DNA sequencing data have revealed that mutation in the TP53 gene is frequent in HNSCC, occurring in up to 85% of human papillomavirus (HPV)-negative primary tumors, and where TP53 mutations are associated with poor response to the radio- and/or chemo- therapies and decreased survival [50,90,91]
Summary
The p53 protein is a homotetrameric transcription factor whose main function is to act as a tumor suppressor regulating the transcriptional program of downstream target genes [1,2]. 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). Mut-p53 proteins are able to aberrantly regulate the transcription of some genes through different mechanisms from wild-type p53, as binding other transcriptional factors and cofactors practically parasitizing their binding sequences onto the target gene promoters [8,9,10] (Figure 1). The small molecules PRIMA-1 and MIRA-1 have been identified by a cell-based screen of two thousand compounds from the National Cancer Institute (NCI) library as targeting p53 mutant forms of p53 and restoring wt-p53 transcriptional activity and having as readout the cell cycle arrest or apoptosis of tumor cells (Figure 1) [27]. To test APR-246 efficacy, patients carrying mutations in p53 are enrolled in diverse clinical studies of phases Ib/II as metastatic esophageal or gastro-esophageal junction cancers (NCT02999893), high-grade serous ovarian cancers (NCT02098343 and NCT03268382) or myeloid neoplasms (NCT03072043) [27]
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