Onecut2, also termed OC-2, is a member of the ONECUT transcription factor family. As a transcription factor, it can widely regulate protein expression associated with cell proliferation, migration, adhesion, differentiation and cell material metabolism [1].

In cancer research, in neuroendocrine prostate cancer (NEPC), ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and drive tumor aggressiveness, partially through regulating hypoxia signaling and tumor hypoxia [2]. In prostate cancer, ONECUT2 activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine variants, and pharmacologic inhibition of it suppresses lineage plasticity reprogramming [3]. In gastric cancer, Helicobacter pylori infection upregulates ONECUT2, which promotes gastric cancer cell stemness via the PPP2R4/AKT/β-catenin signaling pathway [4]. In hepatocellular carcinoma, ONECUT2 acts as an oncogene to facilitate metastasis by transcriptionally upregulating FGF2 and ACLY [5]. In RAS-driven lung adenocarcinoma, ONECUT2 overexpression promotes malignant growth, invasion, xenograft tumorigenesis and bone metastases [6]. Also, targeting ONECUT2 inhibits tumor angiogenesis via down-regulating ZKSCAN3/VEGFA [7].

In conclusion, Onecut2 plays a crucial role in various biological processes related to cell functions. Its dysregulation is significantly associated with multiple cancers, including prostate, gastric, liver, and lung cancers. The findings from these studies, many likely involving in vivo models like KO/CKO mouse models (although not explicitly stated in all references), help in understanding its role in disease development, suggesting it could be a promising target for cancer therapy.

References:

1. Yu, Jia, Li, Dongyang, Jiang, Hua. 2020. Emerging role of ONECUT2 in tumors. In Oncology letters, 20, 328. doi:10.3892/ol.2020.12192. https://pubmed.ncbi.nlm.nih.gov/33101497/

2. Guo, Haiyang, Ci, Xinpei, Ahmed, Musaddeque, Wang, Yuzhuo, He, Housheng Hansen. 2019. ONECUT2 is a driver of neuroendocrine prostate cancer. In Nature communications, 10, 278. doi:10.1038/s41467-018-08133-6. https://pubmed.ncbi.nlm.nih.gov/30655535/

3. Qian, Chen, Yang, Qian, Rotinen, Mirja, You, Sungyong, Freeman, Michael R. . ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer. In Nucleic acids research, 52, 7740-7760. doi:10.1093/nar/gkae547. https://pubmed.ncbi.nlm.nih.gov/38932701/

4. Lin, Mi, Tu, Ru-Hong, Wu, Sheng-Ze, Cao, Long-Long, Li, Ping. 2024. Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway. In Cell death & disease, 15, 497. doi:10.1038/s41419-024-06885-2. https://pubmed.ncbi.nlm.nih.gov/38997271/

5. Liu, Danfei, Zhang, Tongyue, Chen, Xiaoping, Huang, Wenjie, Xia, Limin. 2021. ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. In Cell death & disease, 12, 1113. doi:10.1038/s41419-021-04410-3. https://pubmed.ncbi.nlm.nih.gov/34839358/

6. Ma, Qingyang, Wu, Kai, Li, Hui, Hu, Landian, Kong, Xiangyin. 2019. ONECUT2 overexpression promotes RAS-driven lung adenocarcinoma progression. In Scientific reports, 9, 20021. doi:10.1038/s41598-019-56277-2. https://pubmed.ncbi.nlm.nih.gov/31882655/

7. Zhang, Ligang, Li, Cunjie, Song, Xinran, Wu, Binhua, Deng, Ning. 2024. Targeting ONECUT2 inhibits tumor angiogenesis via down-regulating ZKSCAN3/VEGFA. In Biochemical pharmacology, 225, 116315. doi:10.1016/j.bcp.2024.116315. https://pubmed.ncbi.nlm.nih.gov/38797268/