Super-Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription-Targeted Therapeutic Vulnerability for...

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Gallbladder cancer (GBC) is an aggressive malignancy with limited targeted therapies.
• Super-enhancers (SEs) are critical epigenetic regulators implicated in cancer development.
• Understanding SE reprogramming in GBC is crucial for identifying therapeutic targets.

Purpose of the Study:

• To investigate the role of super-enhancers (SEs) and their regulatory circuitry in gallbladder cancer (GBC).
• To identify key transcription factors (TFs) driving oncogenic SE reprogramming in GBC.
• To explore potential therapeutic strategies targeting identified SE-driven mechanisms.

Main Methods:

• Profiling H3K27ac distribution in GBC tissues and cell lines to map SEs.
• Analyzing core regulatory circuitry (CRC) to identify master transcription factors (TFs).
• Validating TF interactions and assessing therapeutic efficacy of CDK7 inhibition in preclinical models.

Main Results:

• A SOX9 and TCF7L2 autoregulatory loop was identified, driving oncogenic SE reprogramming in a subset of GBC.
• GBC cells with high SOX9/TCF7L2 expression showed dependence on these TFs and enrichment of stemness, ErbB, and Wnt pathway genes.
• Higher levels of SOX9/TCF7L2-high GBC cells correlated with significantly worse patient prognosis.
• Preclinical GBC models with SOX9/TCF7L2 overexpression responded to SE-targeted CDK7 inhibition.

Conclusions:

• This study elucidates novel epigenetic mechanisms in a subset of aggressive GBC.
• The SOX9/TCF7L2 axis serves as a potential prognostic biomarker for GBC.
• Targeting the SOX9/TCF7L2-driven SE network with CDK7 inhibitors offers a promising therapeutic strategy for GBC clinical trials.