Cyp2s1-KO Mouse

CYP2S1, a member of the cytochrome P450 superfamily, is located in chromosome 19q13.2 within a cluster with other CYP2 family members. It is inducible by dioxin, mediated by the Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Nuclear Translocator (ARNT), and is thought to be involved in metabolizing toxic and carcinogenic compounds as well as important endogenous substrates like retinoic acid. It is highly expressed in epithelial cells of extrahepatic tissues frequently exposed to xenobiotics, such as the respiratory, gastrointestinal, and urinary tracts, and the skin [2].

In high-altitude pulmonary edema (HAPE) patients, several CpG sites in the promoter regions of CYP2S1 gene were abnormally methylated. The methylation level of CYP2S1 could effectively predict the risk of HAPE patients [1]. In psoriasis, CYP2S1 might inhibit keratinocyte proliferation and modulate immune response through cytokines, contributing to the development of psoriasis [3]. In BRAFV600E-driven thyroid cancers, CYP2S1 was identified as a synthetic lethal partner of BRAFV600E, and knockdown of CYP2S1 selectively inhibited the proliferation, migration, invasion and tumorigenic potential of BRAFV600E-mutated thyroid cancer cells [4]. In breast cancer, low cytoplasmic CYP2S1 was significantly associated with adverse breast cancer-specific survival [5]. In lung cancer, knockdown of CYP2S1 inhibited cell proliferation, invasion, migration in vitro and tumor growth in vivo, and high CYP2S1 expression was an unfavorable prognostic marker [6]. In colorectal cancer, CYP2S1 knockdown promoted cell proliferation through increasing the level of endogenous prostaglandin E2 (PGE2), which activated β-catenin signaling and enhanced tumor growth in a xenograft mouse model [7].

In conclusion, CYP2S1 plays diverse roles in multiple biological processes and diseases. Its abnormal methylation is related to HAPE, and it is involved in the development and prognosis of various cancers including psoriasis-related skin cancer, thyroid cancer, breast cancer, lung cancer, and colorectal cancer. These findings from different disease models help to understand the biological functions of CYP2S1 and provide potential therapeutic targets for related diseases.

References:

1. Jin, Tianbo, Lu, Hongyan, Zhang, Zhanhao, Yuan, Dongya, He, Yongjun. 2022. CYP2S1 gene methylation among High-altitude pulmonary edema. In Gene, 834, 146590. doi:10.1016/j.gene.2022.146590. https://pubmed.ncbi.nlm.nih.gov/35623478/

2. Saarikoski, Sirkku T, Rivera, Steven P, Hankinson, Oliver, Husgafvel-Pursiainen, Kirsti. . CYP2S1: a short review. In Toxicology and applied pharmacology, 207, 62-9. doi:. https://pubmed.ncbi.nlm.nih.gov/16054184/

3. Sheng, Yujun, Wen, Leilei, Zheng, Xiaodong, Tang, Lili, Zhou, Fusheng. 2020. CYP2S1 might regulate proliferation and immune response of keratinocyte in psoriasis. In Epigenetics, 16, 618-628. doi:10.1080/15592294.2020.1814486. https://pubmed.ncbi.nlm.nih.gov/32924783/

4. Li, Yiqi, Su, Xi, Feng, Chao, Ji, Meiju, Hou, Peng. 2020. CYP2S1 is a synthetic lethal target in BRAFV600E-driven thyroid cancers. In Signal transduction and targeted therapy, 5, 191. doi:10.1038/s41392-020-00231-6. https://pubmed.ncbi.nlm.nih.gov/32913191/

5. Aiyappa-Maudsley, Radhika, Storr, Sarah J, Rakha, Emad A, Ellis, Ian O, Martin, Stewart G. 2022. CYP2S1 and CYP2W1 expression is associated with patient survival in breast cancer. In The journal of pathology. Clinical research, 8, 550-566. doi:10.1002/cjp2.291. https://pubmed.ncbi.nlm.nih.gov/35902379/

6. Guo, Huan, Zeng, Baozhen, Wang, Liqiong, Song, Xin, Zhang, Peixian. . Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration. In Cancer biomarkers : section A of Disease markers, 32, 531-539. doi:10.3233/CBM-210189. https://pubmed.ncbi.nlm.nih.gov/34275895/

7. Yang, Chao, Li, Changyuan, Li, Minle, He, Lin, Wan, Chunling. 2014. CYP2S1 depletion enhances colorectal cell proliferation is associated with PGE2-mediated activation of β-catenin signaling. In Experimental cell research, 331, 377-86. doi:10.1016/j.yexcr.2014.12.008. https://pubmed.ncbi.nlm.nih.gov/25557876/