FBXO2 targets glycosylated SUN2 for ubiquitination and degradation to promote ovarian cancer development

Abstract

SAD1/UNC84 domain protein-2 (SUN2) plays a tumor suppressor role in various types of cancer by inhibiting cancer cell proliferation, migration and promoting apoptosis. However, the post-translational regulation of SUN2 and the cellular mechanism responsible for its proteasomal degradation remains largely unknown. Here, we show that FBXO2, an E3 ubiquitin ligase of the F-box proteins (FBPs) family targets glycosylated SUN2 for ubiquitination and degradation via the ubiquitin-proteasome system (UPS). By integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Encyclopedia of Cancer Cell Lines (CCLE) databases, we revealed that FBXO2 was selectively highly expressed in ovarian cancer (OV) tissues and cells. Patients with relatively high FBXO2 expression levels were associated with worse prognosis. Manipulation of the expression of FBXO2 affecting ovarian cancer cell proliferation, migration/invasion in vitro, and tumor growth in mice in vivo. The transcription factor SOX6 promoted FBXO2 expression by recognizing a putative response element localized on the promoter region of FBXO2. Abnormally highly expressed FBXO2 recognized and targeted glycosylated SUN2 protein for ubiquitination-depended degradation to prevent cell apoptosis, promote cell proliferation, and ultimately promote the progression of OV. Thus, we revealed a new SOX6-FBXO2-SUN2 axis that contributed to the development of OV, and targeting this axis may represent an effective OV treatment strategy.

A membrane sensing mechanism couples local lipid metabolism to protein degradation at the inner nuclear membrane

“…Prior work has shown that Sun2 is targeted for degradation by the proteasome (Ji et al, 2022; Kim et al, 2015; Loveless et al, 2015). A degradation mechanism triggered by reduced INM association of the AH of Sun2 would explain the lower steady state levels of full length Sun2 protein in CTDNEP1 KO cells (see Figure 2D).…”

F-box and leucine-rich repeat 6 promotes gastric cancer progression via the promotion of epithelial-mesenchymal transition

“…The FBPs are substrate receptors for the SCF E3 ubiquitin ligase and play a critical role in recognizing and recruiting polyubiquitinated substrate proteins[ 18 ]. Several studies have reported that FBPs are strongly associated with human cancers and activity of the pertinent oncogenes[ 19 , 20 ]. Reportedly, FBXL16 mechanistically promotes cell growth and migration through the antagonization of the activity of FBW7 and enhancement of the stability of c-Myc[ 21 ].…”

The E3 ligase subunit FBXO45 binds the interferon-λ receptor and promotes its degradation during influenza virus infection

“…The identification of phosphorylation sites within the cytoplasmic or soluble region of IFNLR1 may be important given that F-box proteins are recruited to substrates through phosphosite recognition. However, there may be other posttranslational modifications within this region such as glycosylation that have been described to enhance substrate–SCF complex engagement within the FBXO family ( 29 , 30 ). Nevertheless, a precise mapping of binding motifs within the IFNLR1 cytoplasmic domain by FBXO45 will require additional analysis using recombinant interactors and perhaps structural studies.…”