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Updated: Jul 6, 2026
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Interplay and cooperation between GLI2 and master transcription factors promote progression of esophageal squamous
Yin-Qiao Liu1, Ze-Jun Zheng2, Wang-Kai Fang3
1Department of Clinical Laboratory Medicine, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, the Cancer Hospital of Shantou University Medical College, Shantou 515041, China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, China.
Abstract:
The establishment of gene expression programs that drive cell identity is governed by tightly regulated transcription factors (TFs) that engage in auto- and cross-regulation in a feedforward manner, forming core regulatory circuitries (CRCs). Here, we identify and validate an important interconnected CRC formed by three master TFs-GLI2, TP63, and RUNX1-in esophageal squamous cell carcinoma (ESCC). Furthermore, master TFs co-bind to their own and each other's super-enhancers, forming an interconnected auto-regulatory loop. Mechanistically, these master TFs occupy the majority of ESCC super-enhancers and cooperatively orchestrate the ESCC transcription program. Functionally, GLI2, a master TF, is essential for ESCC viability, migration, invasion, and the growth of xenograft tumors. Moreover, the overexpression of GLI2 is significantly associated with shorter overall survival of patients with ESCC. Downstream, this CRC apparatus coordinately regulates gene expression networks in ESCC, controlling important cancer-promoting pathways, including Hedgehog, glycolysis, and epidermal growth factor receptor signaling pathways. Together, these findings offer significant mechanistic insights into the transcriptional dysregulation in ESCC and recognize GLI2 as a potential therapeutic target and prognostic marker for ESCC. More importantly, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.
Insights
A core regulatory circuitry (CRC) involving GLI2, TP63, and RUNX1 TFs drives esophageal squamous cell carcinoma (ESCC). GLI2 is crucial for ESCC progression and patient survival, highlighting its potential as a therapeutic target.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Gene expression programs establish cell identity through transcription factors (TFs) forming core regulatory circuitries (CRCs).
- Understanding CRCs is vital for deciphering cancer development and identifying therapeutic targets.
Purpose of the Study:
- To identify and validate a key CRC in esophageal squamous cell carcinoma (ESCC).
- To elucidate the functional role of this CRC and its master TFs in ESCC pathogenesis.
- To assess the potential of GLI2 as a prognostic marker and therapeutic target in ESCC.
Main Methods:
- Identification and validation of master TFs (GLI2, TP63, RUNX1) and their regulatory interactions in ESCC.
- Analysis of TF binding to super-enhancers using ChIP-seq.
- Functional assays to determine the role of GLI2 in ESCC cell viability, migration, invasion, and tumor growth.
- Correlation analysis between GLI2 expression and patient survival data.
Main Results:
- An interconnected CRC formed by GLI2, TP63, and RUNX1 was identified in ESCC.
- These master TFs co-occupy and auto-regulate each other's super-enhancers, orchestrating the ESCC transcription program.
- GLI2 is essential for ESCC viability, migration, invasion, and xenograft tumor growth.
- GLI2 overexpression correlates with shorter patient survival.
- The CRC regulates cancer-promoting pathways like Hedgehog, glycolysis, and EGFR signaling.
Conclusions:
- The GLI2-TP63-RUNX1 CRC is a critical determinant of ESCC transcriptional programs.
- GLI2 serves as a potential prognostic marker and therapeutic target for ESCC.
- Downstream genes and pathways regulated by this CRC offer additional therapeutic avenues for ESCC.
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