Dual-Regulated Mechanism of EZH2 and KDM6A on SALL4 Modulates Tumor Progression via Wnt/β-Catenin Pathway in Gastric
Lei Ren1,2, Hong Deng1, Yu Jiang3,4
1Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Background:
SALL4 has been demonstrated in many cancers and participated in tumorigenesis and tumor progression, however, its expression and function still remain ambiguous in GC, especially its upstream mechanistic modulators.
Purpose:
We explored whether the dual mediation of EZH2 and KDM6A could be involved in upstream regulation of SALL4, which promotes GC cell progression via the Wnt/β-catenin pathway.
Method:
Analysis of discrepant gene expression in GC and normal gastric tissues from The Cancer Genome Atlas (TCGA) dataset. GC cell lines were transfected by siEZH2 and siKDM6A, the transduction molecules of KDM6A/EZH2-SALL4-β-catenin signaling were quantified 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 including T stage (local invasion), N stage (lymph node metastasis), M stage (distant metastasis), 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 first proposed and demonstrated that SALL4 promoted GC cell progression via the Wnt/β-catenin 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.
Insights
This study reveals that SALL4 drives gastric cancer (GC) progression through the Wnt/β-catenin pathway. Its regulation by EZH2 and KDM6A offers a new therapeutic target for GC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- * The role of SALL4 in gastric cancer (GC) tumorigenesis and progression is not fully understood, particularly its upstream regulatory mechanisms.
- * Identifying key modulators of SALL4 is crucial for understanding GC development.
Purpose of the Study:
- * To investigate the potential involvement of EZH2 and KDM6A in the upstream regulation of SALL4 in GC.
- * To elucidate how this regulatory axis influences GC cell progression via the Wnt/β-catenin pathway.
Main Methods:
- * Analysis of gene expression data from The Cancer Genome Atlas (TCGA) comparing GC and normal gastric tissues.
- * In vitro experiments involving transfection of GC cell lines with siEZH2 and siKDM6A.
- * Quantification of signaling molecules within the KDM6A/EZH2-SALL4-β-catenin pathway in GC cells.
Main Results:
- * SALL4 was significantly upregulated in GC tissues compared to normal tissues and correlated with various pathological stages and patient survival.
- * Elevated SALL4 levels in GC cells promoted cancer progression and invasion, mediated by the Wnt/β-catenin pathway.
- * KDM6A and EZH2 were found to differentially regulate SALL4 expression, impacting the Wnt/β-catenin signaling.
Conclusions:
- * SALL4 promotes gastric cancer cell progression through the Wnt/β-catenin pathway.
- * This pathway is subject to dual regulation by EZH2 and KDM6A on SALL4.
- * The identified EZH2-SALL4-KDM6A-Wnt/β-catenin axis represents a novel and potentially targetable mechanism in gastric cancer.
Related Concept Videos
02:23Abnormal Proliferation
02:54Canonical Wnt Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:33Pleiotropy
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...