Spin1-KO Mouse

Spin1, also known as Spindlin1, is a histone methylation reader. It epigenetically controls multiple tumorigenesis-associated signaling pathways like Wnt, PI3K/AKT, and RET, and is thus of great importance in cancer-related biological processes. It is also a transcriptional coactivator with critical functions in embryonic development [1,2].

In cancer research, Spin1 depletion in non-small cell lung cancer (NSCLC) cells inhibited cell proliferation, decreased the percentage of cells in the G2/M phase, suppressed cell migration and invasion, and increased radiosensitivity. Mechanistically, it was found to facilitate MDM2-mediated FOXO3a ubiquitination and degradation, leading to upregulation of forkhead box M1 (FOXM1) [3]. In liver cancer, Spin1 was highly expressed, modulated abnormal lipid metabolism by increasing intracellular triglycerides, cholesterols, and lipid droplets, and enhanced tumor growth through SREBP1c-triggered FASN signaling [4]. In human seminoma cells, Spin1 overexpression reduced apoptosis and upregulated CYCD1, a downstream target of the PI3K/AKT pathway, indicating its pro-oncogenic role [5]. Also, Spin1 ablation in human cancer cells activated p53, suppressed cell growth, reduced clonogenic ability, and induced apoptosis by sequestering uL18 in the nucleolus, preventing its interaction with MDM2 and alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53 [6].

In conclusion, Spin1 plays essential roles in tumorigenesis, DNA damage repair, and chemoresistance in various cancers. The use of gene knockout or knockdown models in these studies has been crucial in revealing its oncogenic functions and associated molecular mechanisms, providing potential therapeutic targets for cancer treatment.

References:

1. Li, Di, Guo, Jihua, Jia, Rong. 2021. Histone code reader SPIN1 is a promising target of cancer therapy. In Biochimie, 191, 78-86. doi:10.1016/j.biochi.2021.09.002. https://pubmed.ncbi.nlm.nih.gov/34492335/

2. Wang, Yukun, Li, Mengyao, Chen, Yuhan, Liu, Xiuhua, Wu, Chen. 2024. SPIN1 facilitates chemoresistance and HR repair by promoting Tip60 binding to H3K9me3. In EMBO reports, 25, 3970-3989. doi:10.1038/s44319-024-00219-1. https://pubmed.ncbi.nlm.nih.gov/39090319/

3. Zhong, Min, Fang, Zhi, Zou, Juntao, Xiang, Xiaojun, Fang, Ziling. 2024. SPIN1 accelerates tumorigenesis and confers radioresistance in non-small cell lung cancer by orchestrating the FOXO3a/FOXM1 axis. In Cell death & disease, 15, 832. doi:10.1038/s41419-024-07225-0. https://pubmed.ncbi.nlm.nih.gov/39548064/

4. Zhao, Man, Bu, Yanan, Feng, Jinyan, Wang, Jiapei, Zhang, Xiaodong. 2019. SPIN1 triggers abnormal lipid metabolism and enhances tumor growth in liver cancer. In Cancer letters, 470, 54-63. doi:10.1016/j.canlet.2019.11.032. https://pubmed.ncbi.nlm.nih.gov/31790762/

5. Janecki, Damian Mikolaj, Sajek, Marcin, Smialek, Maciej Jerzy, Kurpisz, Maciej, Jaruzelska, Jadwiga. 2018. SPIN1 is a proto-oncogene and SPIN3 is a tumor suppressor in human seminoma. In Oncotarget, 9, 32466-32477. doi:10.18632/oncotarget.25977. https://pubmed.ncbi.nlm.nih.gov/30197756/

6. Fang, Ziling, Cao, Bo, Liao, Jun-Ming, Xiong, Jianping, Lu, Hua. 2018. SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer. In eLife, 7, . doi:10.7554/eLife.31275. https://pubmed.ncbi.nlm.nih.gov/29547122/