High‐risk endometrial cancer proteomic profiling reveals that FBXW7 mutation alters L1CAM and TGM2 protein levels

Abstract

BACKGROUND: FBXW7 is frequently somatically mutated in grade 3 endometrioid endometrial cancers (G3EECs) and serous endometrial cancers (SECs), which are high-risk cancers associated with poor outcomes and in need of novel treatment options. The aim of this study was to determine the proteomic effects of 3 FBXW7 mutations in high-risk endometrial cancers (ECs). METHODS: Clustered regularly interspaced short palindromic repeats (CRISPR) editing was used to generate 3 HEC-50B G3EEC derivative cell lines, each of which harbored 1 FBXW7 mutation, and to revert an endogenous FBXW7 mutation in HEC-1-B grade 2 endometrioid endometrial cancer (G2EEC) cells to the wild-type genotype. Proteomic profiling based on liquid chromatography-tandem mass spectrometry was used to determine protein differences between the HEC-50B derivative lines and parental cells. Western blot analysis was performed to assess differential protein levels of CRISPR-edited derivative lines originating from HEC-50B, ARK1 (SEC), ARK4 (SEC), HEC-1-B, and JHUEM-1 (G2EEC) cell lines in comparison with parental cells. RESULTS: Results of this study demonstrated the effects of FBXW7 mutations on the proteome and phosphoproteome of HEC-50B G3EEC cells and highlighted proteins that also exhibited altered levels in FBXW7mutated ARK1 and ARK4 SEC cells, including 2 potentially druggable proteins: L1 cell adhesion molecule (L1CAM) and transglutaminase 2 (TGM2). Furthermore, they demonstrated that reversion of an endogenous FBXW7 mutation to the wild-type genotype in JHUEM-1 and HEC-1-B G2EEC cells resulted in decreased L1CAM and TGM2 protein levels. CONCLUSIONS: L1CAM and TGM2 protein levels are affected by FBXW7 mutations in ECs.

Transcription factor FOXP4 inversely governs tumor suppressor genes and contributes to thyroid cancer progression

“…These genes contribute to cancer cell proliferation, and their accumulation can be triggered by FBXW7 mutations and deletions. Mutations and allelic deletions of FBXW7 are frequently observed in a variety of human cancers [ [30] , [31] , [32] ]. Exonic mutations in FBXW7 in differentiated and poorly differentiated thyroid carcinoma [ 33 ], as well as FBXW7 deficiency in patients with follicular type TC [ 34 ] were found through genome sequencing.…”

The Role of FBXW7 in Gynecologic Malignancies

“…FBXW7 mutations have been shown to affect the levels of two druggable proteins: L1 cell adhesion molecule (L1CAM) and transglutaminase 2 (TGM2) [137]. Interestingly, Lehrer and Rheinstein concur with Urick et al [137] in that L1CAM may be a promising druggable target in EC but did not show any relationship between TGM2 expression, FBXW7 mutations and EC survival. This suggests that, when compared to L1CAM, TGM2 might not be of as much value as a druggable target [138].…”

“…Novel insight into proteomic changes associated with FBXW7 mutation in serous ECs include the identification of PADI2 as a potential therapeutic target for these tumors [136]. FBXW7 mutations have been shown to affect the levels of two druggable proteins: L1 cell adhesion molecule (L1CAM) and transglutaminase 2 (TGM2) [137]. Interestingly, Lehrer and Rheinstein concur with Urick et al [137] in that L1CAM may be a promising druggable target in EC but did not show any relationship between TGM2 expression, FBXW7 mutations and EC survival.…”

Large-scale genomic analysis of the domestic dog informs biological discovery

“…In humans, FBXW7 mutations are associated with tumor promotion in multiple types of cancers. Moreover, proteomic profiling of FBXW7 mutant tumors aids the identification of potential downstream therapeutic targets, suggesting this gene could provide a viable therapeutic target in dogs ( Urick and Bell 2020 ; Kawaguchi et al 2021 ; Urick et al 2021 ).…”