Gut microbiota-mediated hsa_circ_0126925 targets BCAA metabolic key enzyme BCAT2 in exacerbating the progression of colorectal cancer

Recent evidence has revealed that a high-fat diet (HFD) can promote the development of tumours, especially colorectal cancer (CRC), by affecting the microbiota. Regulatory circular RNAs (circRNAs) play an important role in modulating host–microbe interactions. However, the specific mechanism by which circRNAs affect cancer progression by regulating these interactions is not yet clear. Here, we report that consumption of a HFD modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein referred to as circ_0126925) in CRC. 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), which leads to reduced degradation of BCAT2. Reducing the targeted degradation of BCAT2 can protect tumours from limited branched-chain amino acids (BCAAs) interference by improving the metabolism of BCAAs in CRC. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of CRC by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host–microbe interactions in CRC. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of CRC by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host–microbe interactions in CRC. The gut microbiota regulated by a high-fat diet can regulate the expression of circ_0126925, thereby promoting the malignant progression of CRC.