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HDAC6 inhibition disrupts HDAC6-P300 interaction reshaping the cancer chromatin landscape

Michela Gottardi Zamperla1, Barbara Illi2, Veronica Barbi1

  • 1Laboratory of Epigenetics, Istituti Clinici Scientifici Maugeri IRCCS, 27100, Pavia, Italy.

Clinical Epigenetics
|August 18, 2024
PubMed
Abstract

Insights

Inactivating histone deacetylase 6 (HDAC6) stabilizes P300, altering chromatin and impacting cancer cell survival genes. This suggests targeting the HDAC6-P300 interaction for novel cancer therapies.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Histone deacetylases (HDACs) regulate gene expression and are cancer targets.
  • HDAC6 influences protein stability and chromatin dynamics.
  • The precise role of HDAC6 in cancer gene regulation requires further investigation.

Purpose of the Study:

  • To investigate the effects of HDAC6 inactivation on P300 stabilization.
  • To analyze the subsequent impact on chromatin structure and function in cancer cells.

Main Methods:

  • HDAC6 inactivation using ITF3756, siRNA, or CRISPR/Cas9.
  • Chromatin accessibility analysis (ATAC-seq).
  • Histone acetylation profiling (H3K27Ac ChIP-seq).
  • Transcriptomics, proteomics, and gene ontology analysis.

Main Results:

  • HDAC6 inactivation significantly increased chromatin accessibility and histone H3 acetylation.
  • Gene expression changes were observed in proliferation, adhesion, migration, and apoptosis pathways.
  • HDAC6 inactivation led to P300 stabilization and downregulation of key cancer survival genes.

Conclusions:

  • HDAC6 inactivation profoundly alters the cancer cell chromatin landscape.
  • P300 stabilization contributes to the anticancer effects of HDAC6 inhibition.
  • Targeting the HDAC6-P300 interaction presents a novel therapeutic strategy for cancer treatment.
Keywords:
ApoptosisCancerCell cycleDeacetylase inhibitorsHATHDACHistone acetylationProliferationTumorigenesis

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