Functional characterization of FBXL7 as a novel player in human cancers

Abstract

F-box and leucine-rich repeat protein 7 (FBXL7), an F-box protein responsible for substrate recognition by the SKP1-Cullin-1-F-box (SCF) ubiquitin ligases, plays an emerging role in the regulation of tumorigenesis and tumor progression. FBXL7 promotes polyubiquitylation and degradation of diverse substrates and is involved in many biological processes, including apoptosis, cell proliferation, cell migration and invasion, tumor metastasis, DNA damage, glucose metabolism, planar cell polarity, and drug resistance. In this review, we summarize the downstream substrates and upstream regulators of FBXL7. We then discuss its role in tumorigenesis and tumor progression as either an oncoprotein or a tumor suppressor, and further describe its aberrant expression and association with patient survival in human cancers. Finally, we provide future perspectives on validating FBXL7 as a cancer biomarker for diagnosis and prognosis and/or as a potential therapeutic target for anticancer treatment.

Fig. 1. The domain structures of FBXL7.

FBXL7, located on chromosome 5p15.1, encodes a 491 amino-acid protein that consists of an F-box motif for SKP1 binding and 11 LRR repeats at the C-terminus. The FQ motif for FBXL18 binding and ubiquitination modification site on K109 are indicated. LRR: leucine-rich repeats.

Fig. 2. The upstream regulatory factors and the downstream substrates of FBXL7.

FBXL7 is regulated by several upstream factors and targets various substrates for ubiquitination and degradation to regulate multiple biological processes. Dashed lines: The lncRNA KCNQ1OT1-hsa-miR-520g-3p axis and mmu-miR-1936 are predicted to regulate FBXL7 by bioinformatic analysis, which requires further experimental confirmation.

Fig. 3. The expression levels of FBXL7 between human tumor tissues and their corresponding normal tissues.

The levels of FBXL7 transcripts are markedly altered in various human cancer tissues, compared to their corresponding normal controls, based on the analysis of Gene Expression Profiling Interactive Analysis (GEPIA) database with tumor and normal tissue samples from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. The number of tumor (T) and normal (N) tissues is indicated. BLCA, bladder urothelial carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD, colon adenocarcinoma; GBM, glioblastoma multiforme; KICH, kidney chromophobe; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PARD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma. TPM: transcripts per million; *p < 0.05, one-way ANOVA.

Fig. 4. High FBXL7 expression predicts a poor patient survival in a variety of human cancers.

FBXL7 expression is markedly associated with patient survival in various cancers according to the Human Protein Atlas database. Blue line: low FBXL7 expression; red line: high FBXL7 expression. The p-value for the log-rank test is indicated.