The role of gut microbiome in mutant p53 oncogenic activity modulation
The role of p53 in the maintenance of cell homeostasis and in the control of its proliferation is well-known. The longest recognized activity of the wild type form of p53 is the tumour-suppressive one. Acting both as a transcription factor and as a direct effector, p53 promotes the arrest of cell-cycle, apoptosis or senescence when severe damages in the DNA or stress conditions are detected. But the activity of p53 can have alternative outcomes too. Indeed, this factor can contribute to cell survival through the expression of its target genes when the cell experiences mild levels of stress. This allows the cell to rejoin the normal population after the elimination of the damage.
Multiple forms of cancer lack the presence of a wild type form of p53 and its regulative activity. However, some types of tumours are characterised by a gain-of-function mutation of p53. Thus, not only p53 does not act as a tumour suppressor but promotes cancer cells proliferation firsthand.
Kadosh et al. focused on two different p53 gain-of-function mutants (R172H and R270H). They demonstrated the modulatory effect of gut microbiota and of one of its metabolic products, gallic acid, on the aforementioned p53 mutants activity. The study was conducted on CKIa-deleted and APCmin mouse models and organoids. In both gut epithelium tumours models, the same p53 mutation turned out having two opposite outcomes: in the proximal gut it reverted its pro-oncogenic effect and restored the differentiation ability of the epithelium, while in the distal gut it promoted uncontrolled proliferation and dysplasia. Analysis of the enterocytes transcriptome clarified that, in the proximal gut, p53 mutant inhibits proliferation by blocking the WNT-pathway by disengaging TCF4 from gene promoters.
The duality of this behaviour has been connected to the metabolic activity of microbiota since, after antibiotic treatment, mouse models showed a normal phenotype in the whole intestinal tract. The load of microbes in the gastrointestinal tract increases leading to the distal regions, so ileum and colon are more affected by the negative modulation of gut microbiome on p53 mutants. Further experiments demonstrated that gallic acid alone can lead to the impairment of the ability of mutant p53 to suppress WNT-driven hyperactivation.
Lactobacillus plantarum and Bacillus subtilis are the gallic acid producers in humans. Interestingly, abundant copies of the gene encoding gallic acid are present in ileum and colon while a few of them are found in the jejunum. Moreover, the supplementation of jejunum epithelium with the same metabolite led to an oncogenic transformation of the gut epithelium phenotype.
All the collected evidence allowed the group to hypothesize that the activity of R172H and R270H p53 mutants is plastic. The fact that this versatility is mediated by a gut microbiota metabolite makes it even more interesting. Indeed, both gallic acid producers and gallic acid itself could be identified as targets for anti-tumoural therapies. They could range from dietary restriction to avoid polyphenols, that are rich in gallic acid, to inhibitors and antagonists of gallic acid. Eventually, the insight of this mechanism lays the foundation to the understanding of the role that other gut microbiota-derived metabolites could have in the modulation of p53. This additional knowledge would amplify the library of potential cancer therapeutic targets.