Aldh6a1, short for aldehyde dehydrogenase 6 family member A1, is a mitochondrial methylmalonate semialdehyde dehydrogenase. It is involved in propionyl-CoA metabolism, an important metabolic pathway that may impact central carbon metabolism and energy metabolism [1,3].

In hepatocellular carcinoma (HCC), Aldh6a1 downregulation leads to decreases in Pro-CoA and its derivative propionyl-L-carnitine, which is tightly associated with HCC development. Functionally, Aldh6a1-mediated Pro-CoA metabolism suppresses HCC proliferation in vitro and impairs hepatocarcinogenesis in mouse models. Mechanistically, Aldh6a1-generated Pro-CoA suppresses citrate synthase activity, reducing tricarboxylic acid cycle flux, impairing mitochondrial respiration and membrane potential, and decreasing ATP production [1]. In clear cell renal cell carcinoma (ccRCC), low expression of Aldh6a1 is correlated with poor survival, and its overexpression significantly attenuates cell proliferation and migration [4]. In colon cancer, Aldh6a1 is low-expressed, and overexpressing it weakens cell vitality, migration, and invasion while facilitating apoptosis by down-regulating the RAS/RAF/MEK/ERK pathway-related markers [2].

In conclusion, Aldh6a1 plays a crucial role in regulating metabolic processes and cell behaviors. Through gene knockout or knockdown studies in mouse models, it has been revealed that Aldh6a1 has tumor-suppressive effects in HCC, ccRCC, and colon cancer. These findings provide potential diagnostic and prognostic biomarkers and suggest Aldh6a1-related metabolic pathways as potential therapeutic targets for these cancers [1,2,4].

References:

1. Sun, Jiaqi, Ding, Jun, Shen, Qingsong, Zhang, Peng, Huang, Zan. 2022. Decreased propionyl-CoA metabolism facilitates metabolic reprogramming and promotes hepatocellular carcinoma. In Journal of hepatology, 78, 627-642. doi:10.1016/j.jhep.2022.11.017. https://pubmed.ncbi.nlm.nih.gov/36462680/

2. Li, Xiang, Wang, Nan, Wu, Yutong, Liu, Yidan, Wang, Ruoyu. 2022. ALDH6A1 weakens the progression of colon cancer via modulating the RAS/RAF/MEK/ERK pathway in cancer cell lines. In Gene, 842, 146757. doi:10.1016/j.gene.2022.146757. https://pubmed.ncbi.nlm.nih.gov/35907565/

3. Shin, Heon, Cha, Hyun-Jeong, Lee, Min Jung, Kim, Hoguen, Paik, Young-Ki. 2020. Identification of ALDH6A1 as a Potential Molecular Signature in Hepatocellular Carcinoma via Quantitative Profiling of the Mitochondrial Proteome. In Journal of proteome research, 19, 1684-1695. doi:10.1021/acs.jproteome.9b00846. https://pubmed.ncbi.nlm.nih.gov/31985234/

4. Lu, Jun, Chen, Zhan, Zhao, Hu, Chen, Shushang, Shao, Jichun. 2020. ABAT and ALDH6A1, regulated by transcription factor HNF4A, suppress tumorigenic capability in clear cell renal cell carcinoma. In Journal of translational medicine, 18, 101. doi:10.1186/s12967-020-02268-1. https://pubmed.ncbi.nlm.nih.gov/32093682/