Gut microbiota-mediated hsa_circ_0126925 targets BCAA metabolic enzyme BCAT2 to exacerbate colorectal cancer progression

  • Mol Cancer Res. 2024 Dec 6. doi: 10.1158/1541-7786.MCR-24-0434.
Huihui Yao  1 ,  Jiancheng Xu  2 ,  Aina Zhou  3 ,  Danyang Shen  1 ,  Qiuchen Dong  4 ,  Xiaodong Yang  5 ,  Mengyu Li  6 ,  Xiuwei Mi  1 ,  Yang Lu  1 ,  Runze Zhong  1 ,  Xinyu Shi  1 ,  Qingliang Tai  1 ,  Guoliang Chen  7 ,  Bo Shi  1 ,  Liang Sun  8 ,  Diyuan Zhou  7 ,  Yizhou Yao  1 ,  Songbing He  1
Affiliations
  • 1. First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 2. Soochow University, Suzhou, Jiangsu, China.
  • 3. Zhongnan Hospital of Wuhan University, Suzhou, Jiangsu, China.
  • 4. Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China.
  • 5. The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
  • 6. Medical College of Soochow University, Suzhou, Jiangsu, China.
  • 7. First Affiliated Hospital of Soochow University, Suzhou, China.
  • 8. Soochow University Medical College, Suzhou, China.
PMID: 39642324 DOI: 10.1158/1541-7786.MCR-24-0434
Abstract

Recent evidence indicates that a high-fat diet (HFD) can promote tumor development, especially colorectal Cancer (CRC), by influencing the microbiota. Regulatory circular RNAs (circRNAs) play 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 HFD modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein referred to as circ_0126925) in CRC. 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 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. 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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