Article Text
Abstract
Objective 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 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.
Design The 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.
Results Amuc_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.
Conclusion Amuc_2172 reprogrammed tumour microenvironment by inducing HSP70 secretion and promoting CTL-related immune response in the process of tumourigenesis.
- COLORECTAL CANCER
- CELL BIOLOGY
- GUT IMMUNOLOGY
- INTERFERON
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Footnotes
YJ, YX, CZ and LY contributed equally.
Contributors All authors are responsible for the overall content as the guarantors. MZ and QZ designed the study; MZ supported the study; YJ, YX, CZ, LY, PJ and GX performed the mice experiments and collected the tissue samples; YX, CZ and PJ conducted the bacterial culture and cell experiments; MZ, YX and CZ performed the immunohistochemistry and TEM experiments; YX, YJ and CZ conducted the flowcytometry and protein mass spectrometry analyses; PJ uploaded the raw data; QZ, MZ and SM wrote and revised the manuscript. All the authors read and approved the final manuscript.
Funding This work was supported by grants from the Natural Science Foundation of China (numbers 82273272 and 81970487) and Shanghai Pujiang Program (number 21PJ1409500).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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