Fbxo44, an F-box protein, is involved in multiple biological functions. It functions as an E3 ubiquitin ligase, playing crucial roles in protein degradation pathways, which are vital for regulating various cellular processes [4,6,7]. It is also associated with the regulation of repetitive element (RE) transcription, an important aspect in maintaining genomic stability [1,3].

In cancer cells, FBXO44 binds H3K9me3-modified nucleosomes at the replication fork and recruits SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. Inhibition of FBXO44/SUV39H1 reactivates REs, leading to DNA replication stress, stimulation of MAVS/STING antiviral pathways, and interferon (IFN) signaling, thereby promoting decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response [1,3]. In adenocarcinoma of the esophagogastric junction, the S-II subtype signature protein FBXO44 promotes tumor progression and metastasis in vitro and in vivo [2]. Additionally, FBXO44-mediated degradation of proteins like RGS2, PXR, and BRCA1 has been identified. For RGS2, FBXO44 acts as the substrate recognition site in the E3 ligase complex for its degradation, and inhibiting the RGS2-FBXO44 interaction could be a therapeutic strategy for diseases like hypertension [4,5,8]. FBXO44 regulates PXR protein abundance through ubiquitination and degradation, which impacts drug-drug interactions [6]. And the SCF(FBXO44) complex is responsible for BRCA1 degradation, potentially contributing to sporadic breast tumor development [7].

In summary, Fbxo44 is essential in protein degradation and RE silencing processes. Its study, especially through functional studies such as those observing the effects of its inhibition in cancer cells, has revealed its significance in cancer-related biological processes. Manipulating Fbxo44-related pathways could potentially offer new therapeutic approaches for cancer treatment as well as for diseases associated with the dysregulation of proteins it targets for degradation, like RGS2-related pathologies [1,2,3,4,5,6,7,8].

References:

1. Shen, Jia Z, Qiu, Zhixin, Wu, Qiulian, Rich, Jeremy N, Spruck, Charles. 2020. FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells. In Cell, 184, 352-369.e23. doi:10.1016/j.cell.2020.11.042. https://pubmed.ncbi.nlm.nih.gov/33357448/

2. Li, Shengli, Yuan, Li, Xu, Zhi-Yuan, Qin, Jiang-Jiang, Cheng, Xiang-Dong. 2023. Integrative proteomic characterization of adenocarcinoma of esophagogastric junction. In Nature communications, 14, 778. doi:10.1038/s41467-023-36462-8. https://pubmed.ncbi.nlm.nih.gov/36774361/

3. Shen, Jia Z, Spruck, Charles. 2021. Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry. In Cell stress, 5, 37-39. doi:10.15698/cst2021.03.245. https://pubmed.ncbi.nlm.nih.gov/33681705/

4. Sjögren, Benita, Swaney, Steven, Neubig, Richard R. 2015. FBXO44-Mediated Degradation of RGS2 Protein Uniquely Depends on a Cullin 4B/DDB1 Complex. In PloS one, 10, e0123581. doi:10.1371/journal.pone.0123581. https://pubmed.ncbi.nlm.nih.gov/25970626/

5. Aryal, Sadikshya, Wong, Cindy Shi Yee, McNabb, Harrison J, Altman, Ryan A, Sjögren, Benita. 2025. Discovery of RGS2-FBXO44 interaction inhibitors using a cell-based NanoBit assay. In Molecular pharmacology, 107, 100030. doi:10.1016/j.molpha.2025.100030. https://pubmed.ncbi.nlm.nih.gov/40199141/

6. Florke Gee, Rebecca R, Huber, Andrew D, Wu, Jing, Pruett-Miller, Shondra M, Chen, Taosheng. 2023. The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation. In Acta pharmaceutica Sinica. B, 13, 4523-4534. doi:10.1016/j.apsb.2023.07.014. https://pubmed.ncbi.nlm.nih.gov/37969738/

7. Lu, Yunzhe, Li, Jiezhi, Cheng, Dongmei, Ye, Qinong, Hu, Yanfen. 2012. The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. In The Journal of biological chemistry, 287, 41014-22. doi:10.1074/jbc.M112.407106. https://pubmed.ncbi.nlm.nih.gov/23086937/

8. McNabb, Harrison J, Gonzalez, Stephanie, Muli, Christine S, Sjögren, Benita. 2020. N-Terminal Targeting of Regulator of G Protein Signaling Protein 2 for F-Box Only Protein 44-Mediated Proteasomal Degradation. In Molecular pharmacology, 98, 677-685. doi:10.1124/molpharm.120.000061. https://pubmed.ncbi.nlm.nih.gov/33008920/