CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells

PLoS One. 2022 Mar 30;17(3):e0262378. doi: 10.1371/journal.pone.0262378. eCollection 2022.

Abstract

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.

MeSH terms

  • Acetyltransferases
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • E1A-Associated p300 Protein / genetics
  • Female
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Humans
  • MCF-7 Cells
  • Receptors, Estrogen* / genetics
  • Receptors, Estrogen* / metabolism

Substances

  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Receptors, Estrogen
  • Acetyltransferases
  • CREB-Binding Protein
  • CREBBP protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human

Grant support

The author(s) received no specific funding for this work.