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NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor

Ramy Ashry1,2, Al-Hassan M Mustafa1,3, Kristin Hausmann4

  • 1Institute of Toxicology, University Medical Centre Mainz, 55131 Mainz, Germany.

Cancers
|July 29, 2023
PubMed

Insights

A novel hydroxamic acid-based histone deacetylase inhibitor (HDACi), KH16, effectively induces apoptosis in pancreatic and colorectal cancer cells. Its efficacy is partly mediated by the NOXA protein, suggesting KH16 as a promising scaffold for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Histone deacetylases (HDACs) are frequently dysregulated in cancer.
  • Small molecule HDAC inhibitors (HDACi) demonstrate cancer cell vulnerability.
  • Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are significant health concerns.

Purpose of the Study:

  • To evaluate a novel hydroxamic acid-based HDACi, KH16 (yanostat), in cancer cells.
  • To investigate the mechanism of KH16-induced apoptosis.
  • To assess the role of the NOXA protein in KH16's anti-cancer effects.

Main Methods:

  • Treatment of PDAC, CRC, and retinal pigment epithelial cells with KH16.
  • Assessment of cell cycle arrest and apoptosis.
  • Analysis of BCL2 family member expression.
  • CRISPR-Cas9 mediated NOXA deletion in PDAC cells.

Main Results:

  • KH16 induced time- and dose-dependent cell cycle arrest and apoptosis in PDAC and CRC cells.
  • Apoptosis induction was linked to altered BCL2 family member expression.
  • KH16 treatment led to NOXA accumulation.
  • Absence of NOXA delayed KH16-induced apoptosis.

Conclusions:

  • KH16 is a potent hydroxamic acid-based HDACi with superior activity against solid tumor cells.
  • NOXA plays a role in KH16-mediated apoptosis.
  • KH16 serves as a scaffold for developing novel HDAC inhibitors with nanomolar activity.
Keywords:
HDACHDACiNOXAapoptosiscolon cancerpancreatic cancer

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