Skp2, also known as S-phase kinase-associated protein 2, is a crucial member of the ubiquitin-proteasome system (UPS). As a component of the Skp2-SCF E3 ligase complex, it conjugates ubiquitin chains to diverse substrates, regulating protein degradation and function, and thus participating in various life processes such as the cell cycle, signal transduction, and DNA repair [1,2,3].

In cancer, genetic mouse models have demonstrated the oncogenic properties of Skp2. For example, in fusion-negative rhabdomyosarcoma, SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program, strongly affecting stemness and tumorigenic features and preventing in vivo tumor growth. SKP2 promotes cell cycle progression and prevents differentiation by targeting p27Kip1 and p57Kip2 [4]. In non-small cell lung cancer, knockdown of Skp2 inhibits cell viability, anchorage-independent growth, and in vivo tumor development. Skp2 promotes cisplatin resistance by mediating MLKL degradation [5]. In pancreatic ductal adenocarcinoma, high expression of SKP2 significantly correlates with decreased survival time, and inhibition of the SKP2/PSPC1 axis impairs cell migration [6].

In conclusion, Skp2 is essential in regulating protein degradation through the UPS, with far-reaching impacts on multiple biological processes. Model-based research, especially gene-knockout studies in mice, has revealed its significant role in cancer development, progression, and drug resistance, highlighting its potential as a therapeutic target in cancer treatment [1,2,3,4,5,6].

References:

1. Feng, Tianyang, Wang, Ping, Zhang, Xiling. 2024. Skp2: A critical molecule for ubiquitination and its role in cancer. In Life sciences, 338, 122409. doi:10.1016/j.lfs.2023.122409. https://pubmed.ncbi.nlm.nih.gov/38184273/

2. Cai, Zhen, Moten, Asad, Peng, Danni, Li, Hong-Yu, Lin, Hui-Kuan. 2020. The Skp2 Pathway: A Critical Target for Cancer Therapy. In Seminars in cancer biology, 67, 16-33. doi:10.1016/j.semcancer.2020.01.013. https://pubmed.ncbi.nlm.nih.gov/32014608/

3. Asmamaw, Moges Dessale, Liu, Ying, Zheng, Yi-Chao, Shi, Xiao-Jing, Liu, Hong-Min. 2020. Skp2 in the ubiquitin-proteasome system: A comprehensive review. In Medicinal research reviews, 40, 1920-1949. doi:10.1002/med.21675. https://pubmed.ncbi.nlm.nih.gov/32391596/

4. Pomella, Silvia, Cassandri, Matteo, D'Archivio, Lucrezia, Locatelli, Franco, Rota, Rossella. 2023. MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting. In Nature communications, 14, 8373. doi:10.1038/s41467-023-44130-0. https://pubmed.ncbi.nlm.nih.gov/38102140/

5. Zhou, Huiling, Zhou, Li, Guan, Qing, Li, Wei, Liu, Haidan. 2023. Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells. In Communications biology, 6, 805. doi:10.1038/s42003-023-05166-6. https://pubmed.ncbi.nlm.nih.gov/37532777/

6. Yuan, Jiahui, Zhu, Zeyao, Zhang, Pingping, Gong, Peng, Zhang, Xianbin. 2024. SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation. In Cancer letters, 587, 216733. doi:10.1016/j.canlet.2024.216733. https://pubmed.ncbi.nlm.nih.gov/38360141/