LncRNA LEF1-AS1/LEF1/FUT8 Axis Mediates Colorectal Cancer Progression by Regulating α1, 6-Fucosylation via Wnt/β-Catenin Pathway

Abstract

Background: Fucosylation alteration is involved in several steps of human cancer pathogenesis. Dysregulated long noncoding RNA (lncRNA) often leads to malignancy in colorectal cancer (CRC). Methods: Differential levels of LEF1-AS1, LEF1 and FUT8 are analyzed by qRT-PCR and western blot. Chip, RIP, EMSA and luciferase reporter assay confirm the direct interaction among LEF1-AS1, MLL1, H3K4me3, LEF1 and FUT8. Functionally, CRC cell proliferation, proliferation, migration and invasion are analyzed by CCK8 assay, colony formation assay, transwell assay and flow cytometry. The xenografts nude mice models, lung metastasis and liver metatstasis are established to determine the effect of LEF1-AS1/LEF1/FUT8 axis on CRC progression in vivo.Results: Here, we identify that LEF1-AS1 and LEF1 are higher in CRC tissues than that in adjacent tissues, as well as upregulated in CRC cell lines than that in normal colorectal cells. Altered levels of LEF1-AS1 modulate LEF1 expression, while altered LEF1 could not regulate LEF1-AS1. LEF1-AS1 recruits MLL1 to the promoter region of LEF1, induces H3K4me3 methylation modification and mediates LEF1 transcription. Furthermore, α1-6 fucosyltransferase FUT8 is overexpressed in CRC tissues and positively correlated to LEF1. FUT8 is a direct target of transcription factor LEF1, which regulates FUT8 level. Altered FUT8 also regulates the core fucosylation of CRC cells, and LEF1-AS1 mediates FUT8 level through activation of Wnt/β-catenin/LEF1 pathway, thereby resulting in β-catenin nuclear translocation. In addition, LEF1-AS1 mediates the proliferation, migration and invasion of CRC cells in vitro. LEF1-AS1 silence hinders the tumorigenesis, liver and lung metastasis of SW620 cells in vivo, while overexpressed FUT8 abolishes the suppressive impact of LEF1-AS1 repression on the biological behavior of SW620 cells. Conclusion: Our studies uncovered a novel mechanism for constitutive LEF1-AS1/LEF1/FUT8 axis in CRC progression by regulating α1, 6-fucosylation via Wnt/β-catenin pathway, and consequently, as a potential therapeutic target in CRC.

Current Research Progress of the Role of LncRNA LEF1-AS1 in a Variety of Tumors

“…They further explored the specific mechanism and established that LEF1-AS1 mainly acts through ceRNA on miR-489 to increase the DIAPH1 level (Cheng Y. et al, 2020). This is consistent with the findings of Qi et al (2021). In colon cancer, a series of cell experiments was conducted to verify the function of LEF1-AS.…”

“…They found that LEF1-AS1 may be beneficial to tumor growth and lung metastasis in vivo (Sun et al, 2020). Qi et al also confirmed the tumorigenic effect of LEF1-AS1 in colorectal cancer (Qi et al, 2021). In terms of HCC, in vivo experiments on tumor-bearing nude mice exhibiting positive WNK1 expression confirmed the interference effect of lncRNA LEF1-AS1 on HCC (Dong et al, 2020).…”

“…Similarly, He et al (He and Qin, 2020) found that silent LEF1-AS1 inhibited the biological function of retinoblastoma cells by inhibiting the expressions of β-catenin and LEF1. The Wnt/β-catenin pathway has also been confirmed to be involved in the occurrence and progression of osteosarcoma (Lu et al, 2020) and colorectal cancer (Qi et al, 2021).…”

“…Many studies have indicated that the lncRNA LEF1-AS1 has a carcinogenic role in the pathogenesis of colorectal cancer (Shi et al, 2019;Cheng Y. et al, 2020;Sun et al, 2020;Qi et al, 2021). Cheng et al downregulated LEF1-AS1 through si-LEF1-AS1 and found that the growth, migration, invasion, and EMT of CRC cells were decreased, and apoptosis was elevated.…”

Role of FUT8 expression in clinicopathology and patient survival for various malignant tumor types: a systematic review and meta-analysis

“…A few studies focused on associations of FUT8 expression with other types of survival (DFS, RFS). For the research on pathways related to FUT8 and tumor survival, many references indicate that FUT8 activates several related signaling pathways, including Ras/MAPKK signaling, c-Met signaling, Akt/mTOR signaling and Wnt/β-catenin signaling, which ultimately lead to hepatocellular carcinoma or colorectal cancer affects the overall survival of patients [ 31 – 33 ]. Höti et al demonstrated that overexpression of FUT8 resulted in upregulation of epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased prostate cancer cells survival [ 34 ].…”