The abstract is read at the publisher; the summary is JClub's.
WY6 disrupts p300–ZEB1 binding and suppresses K80 acetylation, leading to reduced ZEB1 stability and tumor growth suppression in an orthotopic in vivo model.
- Why it matters: p300 inhibitors and bromodomain inhibitors can have limited efficacy and potential adverse effects because they lack targeting selectivity. A safer approach would selectively block p300 interactions with pro-oncogenic factors enriched in neoplastic cells.
- What they did: p300 was shown to acetylate ZEB1 at the conserved K80 residue, stabilizing ZEB1 expression in aggressive cancer cells. The small molecule WY6 binds the p300 TAZ2 domain, disrupts ZEB1–p300 interaction, represses K80 acetylation, and promotes ubiquitination and degradation.
- The result: In vivo, WY6 potently suppresses orthotopic tumor growth without obvious toxic side effects and shows a synergistic effect with PD-1/PD-L1 blockade immunotherapy. K80-acetylated ZEB1 is highly expressed in human cancers and its high-level expression is associated with poor prognosis.
The findingWhy it mattersWhat they didThe result
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