Skp2, also known as S-phase kinase-associated protein 2, is a crucial F-box protein within the ubiquitin-proteasome system (UPS). The UPS is essential for protein degradation, regulating various life processes like the cell cycle, signal transduction, and DNA repair. Skp2, as a component of the Skp2-SCF E3 ligase complex, conjugates ubiquitin chains to substrates, leading to proteasome-mediated proteolysis or functional modulation of the tagged substrates [1,2,3].

In fusion negative rhabdomyosarcoma (FN-RMS), Skp2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program, strongly affecting stemness and tumorigenic features and preventing in vivo tumor growth. This shows its key role in promoting cell cycle progression and preventing differentiation in FN-RMS by targeting p27Kip1 and p57Kip2 [4]. In non-small cell lung cancer (NSCLC), knockdown of Skp2 inhibits cell viability, anchorage-independent growth, and in vivo tumor development. Skp2 promotes cisplatin resistance by mediating the degradation of necroptosis-related regulator MLKL [5]. In pancreatic ductal adenocarcinoma (PDAC), inhibition of the SKP2/PSPC1 axis by SMIP004 impairs cell migration, indicating SKP2 promotes metastasis by suppressing TRIM21-mediated PSPC1 degradation [6].

In conclusion, Skp2 is vital in regulating protein degradation via the UPS, with far-reaching impacts on cell cycle, differentiation, and apoptosis. Gene knockout or conditional knockout mouse models have been instrumental in revealing its role in cancer development and drug resistance, such as in FN-RMS, NSCLC, and PDAC. These findings suggest Skp2 could be a potential therapeutic target in these disease areas.

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/