ΔNp63 bookmarks and creates an accessible epigenetic environment for TGFβ-induced cancer cell stemness and invasiveness
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View abstract on PubMed
Summary
This summary is machine-generated.Transforming growth factor β (TGFβ) signaling stabilizes ΔNp63, enhancing its DNA binding and promoting cancer cell stemness and invasion by altering chromatin accessibility and gene transcription.
Area Of Science
- Cancer Biology
- Epigenetics
- Transcription Factors
Background
- p63 is a transcription factor with diverse functions.
- Transforming growth factor β (TGFβ) signaling influences tumor progression, stemness, and invasion.
- The interplay between TGFβ, p63, and epigenetic modifications in cancer remains unclear.
Purpose Of The Study
- To investigate the role of TGFβ signaling in regulating p63 activity.
- To elucidate the mechanisms by which TGFβ and p63 influence chromatin accessibility and gene transcription.
- To understand the impact of this interaction on cancer cell stemness and invasion.
Main Methods
- Utilized small molecule inhibitors and RNA-silencing for loss-of-function analyses.
- Performed sphere formation assays, chromatin immunoprecipitation, and mRNA expression assays.
- Employed mass spectrometry and co-immunoprecipitation to identify p63 interactors.
Main Results
- TGFβ stimulation enhanced breast cancer cell stemness, which was reduced by ΔNp63 depletion.
- TGFβ signaling, via p38 MAPK, phosphorylated and stabilized ΔNp63, increasing its DNA binding.
- TGFβ modulated histone modifications (H3K27ac/H3K27me3) and recruited p300 to chromatin, promoting accessibility and transcription, an effect dependent on ΔNp63.
Conclusions
- TGFβ signaling, through p38 MAPK and SMAD pathways, phosphorylates and recruits ΔNp63 to specific gene loci.
- This interaction promotes chromatin accessibility and transcription of genes associated with cancer stemness and invasion.
- ΔNp63 plays a crucial role in recruiting histone-modifying enzymes like p300, mediating TGFβ's epigenetic effects.
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