Fusobacterium nucleatum induces chemoresistance in colorectal cancer by inhibiting pyroptosis via the Hippo pathway

ABSTRACT

Chemotherapy resistance is one of the main reasons for the poor prognosis of colorectal cancer (CRC). Moreover, dysbiosis of gut bacteria was found to be a specific environmental risk factor. In this study, enrichment of F. nucleatum was elucidated to be significantly associated with CRC recurrence after chemotherapy. Functional experiments showed that F. nucleatum could inhibit pyroptosis induced by chemotherapy drugs, thereby inducing chemoresistance. Furthermore, mechanistic investigation demonstrated that F. nucleatum could regulate the Hippo pathway and promote the expression of BCL2, thereby inhibiting the Caspase-3/GSDME pyroptosis-related pathway induced by chemotherapy drugs and mediating CRC cell chemoresistance. Taken together, these results validated the significant roles of F. nucleatum in CRC chemoresistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of CRC.

KEYWORDS:

• Fusobacterium nucleatum
• colorectal cancer
• pyroptosis
• chemoresistance
• YAP
• GSDME

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conceptualization, JYF, CBZ, NW; Methodology, NW and LZ; Implementation, NW, LZ, XXL, LHS, YLX, ZRK and LCZ; Software, NW and XXL; Writing – Original Draft, NW; Writing – Review and Editing, JYF, CBZ, NW, LZ, XXL; Funding Acquisition, JYF; Supervision, JYF and CBZ.

Data availability statement

Data supporting these findings are available from the corresponding author upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2333790

Additional information

Funding

We thank all patients and individuals for their participation in our study. This project was supported in part by grants from the National Key R&D Program of China (2020YFA0509200), National Natural Science Foundation of China (81830081, 31970718, 32100138, 82203224), Shanghai Municipal Health Commission, Collaborative Innovation Cluster Project (2019CXJQ02), Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (22CGA17), China Postdoctoral Science Foundation (2022M712124), Shanghai “Rising Stars of Medical Talents” Youth Development Specialist Program (2023-62), Clinical Research Plan of SHDC (SHDC2020CR1034B), Shanghai Sailing Program (21YF1425600) and Innovative research team of high-level local universities in Shanghai.