Acetyltransferase from <i>Akkermansia muciniphila</i> blunts colorectal tumourigenesis by reprogramming tumour microenvironment.

Abstract

The 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 <i>Akkermansia muciniphila</i> has been widely investigated as a probiotic and blunts colitis-associated tumourigenesis in mice, there is little understanding regarding whether <i>A. muciniphila</i> is involved in the PTM of colorectal cancer (CRC). This study investigates whether and how <i>A. muciniphila</i> engages in the PTM of host CRC. The secreting extracellular vesicles from <i>A. muciniphila</i> 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. Amuc_2172, a general control non-derepressible 5-related acetyltransferase of <i>A. muciniphila</i>, was accessible to colorectal cells by macropinocytosis and functioned as an acetyltransferase of Lys14 on histone H3 (H3K14ac). Elevated H3K14ac on <i>Hspa1a</i> 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. Amuc_2172 reprogrammed tumour microenvironment by inducing HSP70 secretion and promoting CTL-related immune response in the process of tumourigenesis.