Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.

Autor: Qiao Z; Department of Chemistry, The University of Chicago, Chicago, IL, USA.; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA., Nguyen LC; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA., Yang D; Department of Chemistry, The University of Chicago, Chicago, IL, USA.; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA.; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA., Dann C; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA., Thomas DM; Department of Chemistry, The University of Chicago, Chicago, IL, USA.; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA., Henn M; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA., Valdespino A; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA., Swenson CS; Department of Chemistry, The University of Chicago, Chicago, IL, USA.; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA., Oakes SA; Department of Pathology, The University of Chicago, Chicago, IL, USA., Rosner MR; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA. mrosner@uchicago.edu., Moellering RE; Department of Chemistry, The University of Chicago, Chicago, IL, USA. rmoellering@uchicago.edu.; Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA. rmoellering@uchicago.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2024 Aug 30. Date of Electronic Publication: 2024 Aug 30.
DOI: 10.1038/s41589-024-01716-z
Abstrakt: Many oncogenic transcription factors (TFs) are considered to be undruggable because of their reliance on large protein-protein and protein-DNA interfaces. TFs such as hypoxia-inducible factors (HIFs) and X-box-binding protein 1 (XBP1) are induced by hypoxia and other stressors in solid tumors and bind to unfolded protein response element (UPRE) and hypoxia-induced response element (HRE) motifs to control oncogenic gene programs. Here, we report a strategy to create synthetic transcriptional repressors (STRs) that mimic the basic leucine zipper domain of XBP1 and recognize UPRE and HRE motifs. A lead molecule, STR22, binds UPRE and HRE DNA sequences with high fidelity and competes with both TFs in cells. Under hypoxia, STR22 globally suppresses HIF1α binding to HRE-containing promoters and enhancers, inhibits hypoxia-induced gene expression and blocks protumorigenic phenotypes in triple-negative breast cancer (TNBC) cells. In vivo, intratumoral and systemic STR22 treatment inhibited hypoxia-dependent gene expression, primary tumor growth and metastasis of TNBC tumors. These data validate a novel strategy to target the tumor hypoxia response through coordinated inhibition of TF-DNA binding.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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