Sult2a1-KO Mouse

SULT2A1, a cytosolic sulfotransferase, is a phase II conjugating enzyme [3]. It is highly expressed in the liver, intestine, and adrenal tissue [4]. SULT2A1 preferentially sulfonates hydroxysteroids like dehydroepiandrosterone, testosterone/dihydrotestosterone, pregnenolone, and cholesterol-derived amphipathic sterol bile acids [4]. It also sulfonates several therapeutic drugs and xenobiotics [4]. Nonsteroid nuclear receptors such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor-alpha, and vitamin D receptor can mediate the transcription induction of SULT2A1 in the enterohepatic system [4].

In hepatocellular carcinoma (HCC), SULT2A1 deficiency promoted chemotherapy resistance and stemness maintenance by activating the AKT signaling pathway, up-regulating the downstream stemness gene c-Myc, facilitating NRF2 expression to reduce ROS accumulation, and the knockdown of NR1I3 was involved in its transcriptional regulation during stemness maintenance. Also, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells, exerting a potential stroma remodeling effect [3]. In addition, the expression of SULT2A1 is extremely downregulated in human HCC tissues, and gain-and loss-of-function studies revealed that it suppresses the metastasis of HCC by regulating the level of 27-hydroxycholesterol (27-OHC), which activates the nuclear factor-κB signaling pathway and promotes HCC metastasis by enhancing Twist1 expression and epithelial-mesenchymal transition [2]. In CCl4-induced liver fibrosis in mice, mangiferin treatment inhibited the expression of SULT2A1 along with other genes related to bile acid metabolism, inflammation, and fibrogenesis, alleviating liver fibrosis [1].

In conclusion, SULT2A1 is crucial in the sulfonation of various endogenous and exogenous compounds. Its dysregulation is associated with HCC metastasis, stemness, and liver fibrosis. Loss-of-function studies in HCC cell models and in vivo mouse models of liver fibrosis have revealed its role in these disease conditions, highlighting its potential as a prognostic biomarker and therapeutic target for HCC metastasis and a relevant factor in liver fibrosis treatment [1,2,3].

References:

1. Zhang, Lijun, Liu, Chuhe, Yin, Liufang, Huang, Cheng, Fan, Shengjie. 2023. Mangiferin relieves CCl4-induced liver fibrosis in mice. In Scientific reports, 13, 4172. doi:10.1038/s41598-023-30582-3. https://pubmed.ncbi.nlm.nih.gov/36914687/

2. He, Taochen, Tao, Baorui, Yi, Chenhe, Lin, Jing, Chen, Jinhong. 2022. 27-Hydroxycholesterol promotes metastasis by SULT2A1-dependent alteration in hepatocellular carcinoma. In Cancer science, 113, 2575-2589. doi:10.1111/cas.15435. https://pubmed.ncbi.nlm.nih.gov/35599597/

3. Peng, Hao, Feng, Kun, Jia, Weilu, Lv, Qingpeng, Zhang, Yewei. 2024. An integrated investigation of sulfotransferases (SULTs) in hepatocellular carcinoma and identification of the role of SULT2A1 on stemness. In Apoptosis : an international journal on programmed cell death, 29, 898-919. doi:10.1007/s10495-024-01938-5. https://pubmed.ncbi.nlm.nih.gov/38411862/

4. Chatterjee, Bandana, Echchgadda, Ibtissam, Song, Chung Seog. . Vitamin D receptor regulation of the steroid/bile acid sulfotransferase SULT2A1. In Methods in enzymology, 400, 165-91. doi:. https://pubmed.ncbi.nlm.nih.gov/16399349/