Colorectal cancer (CRC) is one of the three leading causes of cancer-related death in the world (Dienstmann et al., 2017, Lucas et al., 2017, Wrobel and Ahmed, 2019). In recent years, the therapy of colon cancer has been greatly improved due to the continuous improvement of surgical methods and the advances of radiotherapy and chemotherapy regimens (Snaebjornsson et al., 2017, Iyer et al., 2019). Abnormal regulation of angiogenesis is generally considered to be one of the most important control points of tumor invasion and metastasis, which is an important reason for the occurrence and development of tumors (including CRC) and poor prognosis (Piawah and Venook, 2019, Viallard and Larrivee, 2017, Ramjiawan et al., 2017). Several proteins can serve as biomarkers for predicting the migration and angiogenesis capacity of CRC, such as VEGF, CD31, MMP2, MMP9, ANGPT2, FGF1, and PDGFA (Piawah and Venook, 2019, Viallard and Larrivee, 2017, Ramjiawan et al., 2017). Therefore, it is an important direction to study the molecular mechanism related to the malignant process of CRC.

With the in-depth study of epigenetics, increasing studies have found that ubiquitinating modification of protein post translation by regulating the degradation of specific target protein in tumor related to signal transduction, metabolic regulation, maintenance of stem cell properties plays an important role (Jean-Charles et al., 2016, Jia et al., 2020, Mevissen and Komander, 2017, Li et al., 2021). However, due to the numerous types of ubiquitination modification systems and complex action modes, the regulatory mechanisms in the occurrence and development of CRC have not been clearly analyzed.

Cullin-ring ligases (Crl) are a multi-subunit RING finger family containing E3 ligases, constituting the largest E3. Skp1-cul1-f-box (SCF) E3 ligase, also known as Crl1, is a founding member and the most representative of Crl (Zhao and Sun, 2013). SCF E3 ligase consists of four subunits: the scaffold protein Cul1; a RING component Rbx1; adaptor protein Skp1; and an F-box protein, which is a substrate receptor. F-box proteins directly recognize and bind to substrates, determining the substrate specificity of SCF ubiquitin ligases. F-box proteins are divided into three major subgroups: FBXW subgroup (WD repeat domain), FBXL subgroup (leucine-rich repeat domain), and FBXO subgroup (other domain) (Wang et al., 2014). Previous studies by our group found that F-box protein F-box and WD repeat domain containing 11 (FBXW11) degrades HIC1 tumor suppressor protein through SCF ubiquitinase system, thereby promoting the proliferation and stem cell-like phenotype of colorectal cancer cells (Yao et al., 2021).

FBXW10 is a member of the FBXW subgroup and contains the WD40 domain. The WD40 domain is an abundant domain of FBXW family in human cells, characterized by its ability to mediate protein-protein interactions (Zhang et al., 2019). For example, FBXW7 links to ERK protein through the WD40 region and promotes the ubiquitination of ERK protein (An et al., 2022). In addition, studies have shown that FBXW10 (a member of the F-box protein family involved in E3 ubiquitin ligase activity) can induce ubiquitin-mediated proteasomal degradation of HP1 isotype (Chaturvedi and Parnaik, 2010). Moreover, it has been reported that FBXW10 is abnormally hypermethylated in renal cell carcinoma cell line and RCC tissues, and this feature is only related to Fuhrman grade and tumor stage (Wang et al., 2015). FBXW10 promotes cell proliferation and migration of liver cancer cell lines, and it is also a potential prognostic marker for male liver cancer patients (Luo et al., 2020). TCGA database analysis showed that FBXW10 was highly expressed in CRC. However, the role of FBXW10 in CRC has been rarely reported and the mechanism is unclear.

Our study found that FBXW10 was significantly upregulated in CRC and was involved in the pathogenesis of CRC by affecting cell proliferation, migration, invasion and vascular formation. Mechanistically, FBXW10 degraded large tumor suppressor kinase 2 (LATS2), a cancer suppressor gene, through ubiquitination. Therefore, FBXW10-LATS2 axis has the potential to be used as a therapeutic target for CRC in subsequent studies.