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

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An Invited Commentary to this article was published on 06 March 2023

Abstract

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.

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Funding

This work was supported by the [Southwest medical university] under Grant [2018-ZRQN-093]; [Sichuan Medical Association] under Grant [Q18010].

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Authors and Affiliations

  1. Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China

    Lei Ren & Hong Deng

  2. Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Yu Jiang

  3. Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Taiping Str. 25, Luzhou, 646000, China

    Chunfeng Liu

  4. Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Taiping Str. 25, Luzhou, 646000, China

    Yu Jiang & Chunfeng Liu

  5. Department of Surgery, Klinikum Rechts Der Isar, Technical University of Munich, School of Medicine, Munich, Germany

    Lei Ren

  6. Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, Thalkirchner Str. 36, 80337, Munich, Germany

    Chunfeng Liu

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Ren, L., Deng, H., Jiang, Y. et al. Dual-Regulated Mechanism of EZH2 and KDM6A on SALL4 Modulates Tumor Progression via Wnt/β-Catenin Pathway in Gastric Cancer. Dig Dis Sci 68, 1292–1305 (2023). https://doi.org/10.1007/s10620-022-07790-4

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