Dual-Regulated Mechanism of EZH2 and KDM6A on SALL4 Modulates Tumor Progression via Wnt/β-Catenin Pathway in Gastric Cancer

Abstract

Background: The molecular mechanism underlying the progression of gastric cancer (GC) remains unclear, the overexpression level of SALL4 has been demonstrated in many cancers and participated in tumorigenesis, however, it is still ambiguous for the expression and function of SALL4 in GC, especially its upstream mechanistic modulators.Method: Analysis of discrepant gene expression in GC and normal gastric tissues from The Cancer Genome Atlas (TCGA) dataset. Cultured GC cell lines were treated with siEZH2 and siKDM6A and checked for their in uences on SALL4, the transduction molecules of KDM6A/EZH2-SALL4-β-catenin signaling were quanti ed in the GC cells.Results: Here, we showed that only SALL4 levels of SALL family members were upregulated in nonpaired and paired GC tissues than those in corresponding normal tissues and were associated with its histological types, pathological stages, TNM stages, and overall survival from the TCGA dataset. SALL4 level was elevated in GC cells compared to normal gastric epithelial cell line (GES-1) and was correlated to cancer cell progression and invasion through the Wnt/β-catenin pathway in GC, which levels would be separately upregulated or downregulated by KDM6A or EZH2. Conclusion:We rst proposed and demonstrated that SALL4 promoted GC cell progression via the Wnt/βcatenin pathway, which was mediated by the dual regulation of EZH2 and KDM6A on SALL4. This mechanistic pathway in gastric cancer represents a novel targetable pathway.

SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms

“…This review shows that SALL4 participates not only in the growth, anti-apoptosis, metastasis, and invasion of these cancers but also in drug resistance (Cheng et al 2015a ), EMT (Zhang et al 2018 ), OXPHOS (Tan et al 2019 ), DNA methylation (Yang et al 2012 ) and angiogenesis (Abouelnazar et al 2023a ), in some cases. The expression of SALL4 is regulated by upstream regulators such as THG-1 (Hwang et al 2020 ), MEIS1 (Zargari et al 2020 ), YAP (Bie et al 2020 ), ILF2 (Li et al 2021 ), KDM6A and EZH2 (Ren et al 2023 ) and some members of the microRNA family (Jiang and Wang 2018 ; Chang et al 2020 ; Cheng et al 2015a ; Yan et al 2018 ; Peng et al 2018 ). On the other hand, SALL4 acts as an oncogene via the Wnt/β-catenin pathway (He et al 2016 ), TGF-β/SMAD pathway (Zhang et al 2018 ), Notch pathway (Forghanifard et al 2021 ), PI3K/AKT pathway (Tang et al 2022 ), ERK, STAT3 and NF-κB pathway (Yuan et al 2016 ) in various GIT cancers.…”

“…A recent study has found that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression (Abouelnazar et al 2023a ). SALL4 is associated with clinicopathological features related to GC progression, and it functions via the Wnt/β-catenin pathway (Yang et al 2021a ), which can be mediated by dual regulation of SALL4 by EZH2 and KDM6A (Ren et al 2023 ). Nicotine promotes the stabilization and expression of SALL4 by upregulating the RNA-binding protein interleukin enhancer binding factor 2 (ILF2), which facilitates tumor initiation in esophageal cancer cells (Li et al 2021 ).…”

Inactivation of KDM6A promotes the progression of colorectal cancer by enhancing the glycolysis

“…Currently, KDM6A has been reported to regulate gene expression through both methylation-dependent and methylation-independent mechanisms [ 7 , 8 ]. KDM6A is upregulated in gastric cancer and can regulate the expression of SALL4, thereby promoting the growth and metastasis of gastric cancer [ 9 ]. In renal cell carcinoma, KDM6A can upregulate the expression of autophagy-related genes [ 10 ].…”