Identification of a Novel GRHL3/HOPX/Wnt/beta-Catenin Proto- oncogenic Axis in Squamous Cell Carcinoma of the Esophagus

The transcription factor GRHL3 exerts its tumor suppressor function in esophageal squamous cell carcinoma through regulating HOPX expression and Wnt signaling. The study provides a clear rationale for using targeted therapies against Wnt/beta-catenin pathways in patients with reduced GRHL3 expression. BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor long-term prognosis. The molecular mechanisms underlying the initia-tion and progression of this tumor are largely unknown. The transcription factor GRHL3 functions as a potent tumor sup-pressor in SCC of skin, head, and neck. This study aims to determine whether GRHL3 also plays a role in the homeostasis of the esophageal epithelium and in the development of ESCC. METHODS: The effects of Grhl3 deletion on squamous epithe-lial homeostasis in embryos and adult mice were examined using immunohistochemistry, transmission electron micro-scopy, and real-time polymerase chain reaction. The condi-tionally deleted mice were subsequently used to determine susceptibility to ESCC. Whole-transcriptome sequencing (RNA-seq) was performed on ESCC in wild-type and Grhl3 deleted animals. To decipher the signaling pathways, real-time poly-merase chain reaction, immunohistochemistry, analysis of chromatin immunoprecipitation sequencing, chromatin immunoprecipitation-polymerase chain reaction, and RNA seq datasets were used. Primary human samples were used to validate the findings in the mouse model. RESULTS: Loss of Grhl3 perturbs the proliferation -differentiation balance in the esophageal epithelium, thereby increasing the susceptibility to esophageal carcinogenesis in adult mice. Grhl3 imparts its tumor suppressor function by regulating the expression of HOPX. We have identified the Wnt/ b-catenin pathway as the downstream effectors of GRHL3 and HOPX through our integrated approach using patient-derived ESCC samples and mouse models. CONCLUSIONS: GRHL3 conveys its tumor suppressor function in ESCC through regulating its target gene HOPX, which limits Wnt/b-catenin signaling. Targeted therapies to inhibit this pathway could be a potential treatment strategy for ESCC patients with reduced GRHL3 expression. (Cell Mol Gastro-enterol Hepatol 2023;15:1051-1069; https://doi.org/10.1016/ j.jcmgh.2022.11.009)

Automated summary

The transcription factor GRHL3 functions as a tumor suppressor in esophageal squamous cell carcinoma by regulating HOPX expression and Wnt signaling. The study highlights the potential of targeted therapies against the Wnt/beta-catenin pathways in patients with reduced GRHL3 expression.