Related Experiment Video

Updated: Jun 5, 2026

Assays for Validating Histone Acetyltransferase Inhibitors
09:11

Assays for Validating Histone Acetyltransferase Inhibitors

Published on: August 6, 2020

Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell

William Brazelle1, Jenny M Kreahling, Jennifer Gemmer

  • 1Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

Plos One
|December 24, 2010
PubMed
Abstract

Insights

Histone deacetylase inhibitors (HDACis) reduce checkpoint kinase 1 (Chk1) levels, leading to mitotic entry and cell death in lung cancer. Chk1 inhibition enhances HDACi efficacy, suggesting Chk1 as a predictive biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Histone deacetylase inhibitors (HDACis) show anticancer potential but their mechanisms and resistance pathways remain unclear.
  • Limited clinical efficacy of HDACis necessitates understanding their molecular actions and resistance mechanisms.

Purpose of the Study:

  • To elucidate the molecular mechanisms of HDAC inhibitor (HDACi)-induced cell death in lung cancer.
  • To investigate the role of checkpoint kinase 1 (Chk1) in HDACi response and identify potential biomarkers for HDACi efficacy.

Main Methods:

  • Assessed protein and transcript levels of Chk1 in lung cancer cells treated with various HDACis.
  • Analyzed Chk1 function by examining phosphorylation of cdc25c, cdc2, and expression of cdc25A and phosphorylated histone H3.
  • Investigated the effect of Chk1 overexpression and inhibition on HDACi-induced cell death.
  • Utilized cdc2 inhibitor purvalanol A to block mitotic entry.

Main Results:

  • HDACi treatment markedly reduced Chk1 protein and transcript levels in lung cancer cells.
  • Impaired Chk1 function was observed, leading to decreased inhibitory phosphorylation of cdc25c/cdc2 and increased mitotic entry markers.
  • Chk1 downregulation preceded apoptosis, and its restoration overcame HDACi-induced cell death.
  • Pharmacological inhibition of Chk1 synergized with HDACi LBH589, enhancing cell death.

Conclusions:

  • HDACi-induced cell death is mediated by Chk1 inhibition, promoting mitotic entry.
  • Chk1 serves as a potential early pharmacodynamic marker for assessing HDACi efficacy in clinical settings.

More Related Videos

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...