Recent evidence indicates that a high-fat diet can promote tumor development, especially colorectal cancer, by influencing the microbiota. Regulatory circular RNA (circRNA) plays an important role in modulating host–microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a high-fat diet modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein, referred to as circ_0126925) in colorectal cancer. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumors from limited branched-chain amino acid (BCAA) interference by improving the metabolism of BCAAs in colorectal cancer. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of colorectal cancer by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host–microbe interactions in colorectal cancer.

Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome-related pathology in humans.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
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Supplementary data

Figure S1

S1. Representative images of colon length and rectal bleeding at the endpoint of modelling in AOM/DSS model mice subjected to three different treatment methods.

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Figure S2

S2. IF of the tight junction proteins ZO-1 and Occludin in AOM/DSS model mice subjected to three different treatment methods and IHC staining of the Ki-67 in the colon of mice subjected to two different treatment methods.

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Figure S3

S3. In AOM/DSS model mice, antibiotic treatment significantly attenuated the colon tumorigenesis.

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Figure S4

S4. HFD-modulated gut microbiota of mice and obese patients promote malignant progression of colorectal tumors in Abx pretreated AOM/DSS model mice.

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Figure S5

S5. In vitro, circ_38945 promotes proliferation and migration.

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Figure S6

S6. Stable cells with circ_0126925 knockdown or overexpression.

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Figure S7

Figure S7. Mass spectrometry analysis of the BCAT2, keratin 19 and ACOT7 peptides pulled down by antisense circ_0126925 probes.

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Figure S8

S8. IHC staining of NRF2 in the normal BCAA diet group and the low BCAA diet group.

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Supplementary Table S1

Table S1. Clinical information of 96 patients

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Supplementary Table S2

Table S2. Primers used in RT-qPCR and vitro transcription.

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Supplementary Table S3

Table S3. Information of antibodies.

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Supplementary Table S4

Table S4. RNAi targets sequences.

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Supplementary Table S5

Table S5. Digoxin labeled probes, Cy3 labeled probes, Desthio Biotin-TEG labeled probes

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