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Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a master regulator that
Abstract:
Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/b-catenin target genes, and the pro-metastatic TGFb pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.
Insights
Researchers identified ThPOK, a master transcription factor, as a key regulator suppressing breast cancer metastasis. ThPOK restricts cancer cells to an epithelial state by inhibiting genes driving invasion and spread.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic breast cancer remains a significant clinical challenge.
- Understanding transcriptional deregulation, particularly super-enhancers (SEs), is crucial for identifying cancer dependencies.
- Identifying novel regulators of breast cancer progression is vital for therapeutic development.
Purpose of the Study:
- To identify novel breast cancer dependencies by analyzing the super-enhancer landscape and master regulator activity.
- To investigate the role of T-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK) in breast cancer progression.
Main Methods:
- Integrated analysis of super-enhancer (SE) landscape with master regulator activity inference in breast cancer cell lines.
- Manipulation of ThPOK expression levels in cell lines.
- Analysis of gene expression related to epithelial-mesenchymal transition (EMT), WNT/b-catenin, and TGFb pathways.
Main Results:
- Identified ThPOK (ZBTB7B) as a master regulator recurrently associated with a SE in breast cancer.
- Found ThPOK expression is highest in luminal breast cancer and reduced in basal subtypes.
- Demonstrated that ThPOK suppresses genes involved in EMT, WNT/b-catenin signaling, and TGFb pathway, restricting cells to an epithelial phenotype.
Conclusions:
- ThPOK acts as a master transcription factor that restricts breast cancer cells from acquiring metastatic features.
- ThPOK's repressive function is critical in maintaining an epithelial phenotype and suppressing metastatic potential.
- Targeting ThPOK or its regulatory pathways could offer novel therapeutic strategies for breast cancer metastasis.
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