FBXO44 Regulates FOXP1 Degradation Through AURKA‐Dependent Phosphorylation to Promote Colorectal Cancer Progression

Abstract Emerging evidence highlights the role of SCF E3 ligases, consisting of SKP1, cullin‐1, and F‐box proteins, in cancer biology by regulating the ubiquitination and degradation of key proteins. This study identifies F‐box only protein 44 (FBXO44) as an oncogene in colorectal cancer (CRC). FBXO44 is upregulated in CRC patients and correlates with poor prognosis. Knockdown of FBXO44 inhibits CRC cell proliferation and organoid growth, as well as xenograft tumor growth and AOM/DSS‐induced intestinal tumorigenesis. Conversely, FBXO44 overexpression accelerates tumor growth in vitro and in vivo. Mechanistically, FBXO44 targets Forkhead box protein P1 (FOXP1) for degradation. Aurora kinase A (AURKA) phosphorylates FOXP1 at Ser440, enhancing FBXO44 binding, leading to K48‐linked ubiquitination at K377 and proteasomal degradation. This degradation relieves FOXP1 repression of Cyclin E2, promoting CRC cell proliferation. In summary, FBXO44 is an oncogene that promotes CRC tumorigenesis by degrading FOXP1 and upregulating Cyclin E2, offering a potential therapeutic target for CRC.