Acetyltransferase from Akkermansia muciniphila blunts colorectal tumourigenesis by reprogramming tumour microenvironment

ObjectiveThe protein post-translational modification (PTM) in host cells can be rewritten by bacterial enzymes and represents an unprecedented mechanism in the communication between intestinal flora and the host. Although Akkermansia muciniphila has been widely investigated as a probiotic and blunts colitis-associated tumourigenesis in mice, there is little understanding regarding whether A. muciniphila is involved in the PTM of colorectal cancer (CRC). This study investigates whether and how A. muciniphila engages in the PTM of host CRC. DesignThe secreting extracellular vesicles from A. muciniphila and purified Amuc_2172 were used for different tumourigenesis mice models. Amuc_2172-induced immune activity of CD8(+) cytotoxic T lymphocytes (CTLs) were evaluated in vitro and in vivo. The acetyltransferase activity and downstream target genes of Amuc_2172 were investigated. ResultsAmuc_2172, a general control non-derepressible 5-related acetyltransferase of A. muciniphila, was accessible to colorectal cells by macropinocytosis and functioned as an acetyltransferase of Lys14 on histone H3 (H3K14ac). Elevated H3K14ac on Hspa1a loci promoted the transcription and secretion of heat-shock protein 70 (HSP70) in cancer cells. High level of HSP70 promoted the immune activity of CTLs in vitro and in vivo. Moreover, bioengineered nanoparticles provided a safe and reliable drug delivery strategy of Amuc_2172 for CRC treatment in an allograft mice model. ConclusionAmuc_2172 reprogrammed tumour microenvironment by inducing HSP70 secretion and promoting CTL-related immune response in the process of tumourigenesis.

Automated summary

This study reveals that the gut bacterium A. muciniphila is involved in the post-translational modification of proteins in colorectal cancer (CRC). A specific enzyme, Amuc_2172, is capable of acetylating histone H3 and promoting the expression and secretion of HSP70 in cancer cells, leading to enhanced immune activity of CTLs. Furthermore, bioengineered nanoparticles provide a potential drug delivery strategy for the treatment of CRC.