Enterobacteria impair host p53 tumor suppressor activity through mRNA destabilization

Increasing evidence highlights the role of bacteria in the physiopathology of cancer. However, the underlying molecular mechanisms remains poorly understood. Several cancer-associated bacteria have been shown to produce toxins which interfere with the host defense against tumorigenesis. Here, we show that lipopolysaccharides from Klebsiella pneumoniae and other Enterobacteria strongly inhibit the host tumor suppressor p53 pathway through a novel mechanism of p53 regulation. We found that lipopolysaccharides destabilize TP53 mRNA through a TLR4-NF-kappa B-mediated inhibition of the RNA-binding factor Wig-1. Importantly, we show that K. pneumoniae disables two major tumor barriers, oncogene-induced DNA damage signaling and senescence, by impairing p53 transcriptional activity upon DNA damage and oncogenic stress. Furthermore, we found an inverse correlation between the levels of TLR4 and p53 mutation in colorectal tumors. Hence, our data suggest that the repression of p53 by Enterobacteria via TLR4 alleviates the selection pressure for p53 oncogenic mutations and shapes the genomic evolution of cancer.

Automated summary

There is increasing evidence suggesting the involvement of bacteria in the development of cancer, although the underlying molecular mechanisms are not well understood. In this study, the researchers found that lipopolysaccharides from bacteria such as Klebsiella pneumoniae inhibit the tumor suppressor p53 pathway through a novel mechanism. They discovered that the lipopolysaccharides destabilize TP53 mRNA through the TLR4-NF-kappa B-mediated inhibition of the RNA-binding factor Wig-1. Moreover, they found a correlation between the levels of TLR4 and p53 mutation in colorectal tumors, suggesting that the repression of p53 by bacteria may shape the genomic evolution of cancer.