Histone deacetylase inhibition induces apoptosis in neuroblastoma
Chitra Subramanian1, Anthony W Opipari, Valerie P Castle
1Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
Abstract:
Histone deacetylase inhibitors constitute a promising new treatment for cancer due to their novel site of action and low toxicity. Almost all histone deacetylase inhibitors currently in clinical development have anti-proliferate activities against cells in cultures, and specifically cause cell cycle arrest, differentiation and apoptosis. Interestingly, despite their rapid advance into clinical use, the cellular responses leading to these effects remain unclear. We recently reported that histone deacetylase inhibitor treatment induces apoptosis of neuroblastoma cells by increasing the acetylation of Ku70 in the cytoplasm, resulting in the release of Bax from Ku70. Subsequently, Bax releases cytochrome c from mitochondria causing apoptosis. Here we will discuss these findings and the implications of our model for the further clinical development of histone deacetylase inhibitors in the treatment of cancer.
Insights
Histone deacetylase inhibitors induce cancer cell apoptosis by increasing cytoplasmic Ku70 acetylation, releasing Bax and cytochrome c. This mechanism clarifies their anti-cancer effects and guides future clinical development.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Histone deacetylase inhibitors (HDACi) show promise as cancer therapeutics with novel mechanisms and low toxicity.
- HDACi induce anti-proliferative effects like cell cycle arrest, differentiation, and apoptosis in cancer cells.
- The precise cellular mechanisms underlying HDACi-induced apoptosis remain largely unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which histone deacetylase inhibitors induce apoptosis in neuroblastoma cells.
- To investigate the role of Ku70 acetylation in mediating the apoptotic pathway triggered by HDAC inhibitors.
Main Methods:
- Treatment of neuroblastoma cells with histone deacetylase inhibitors.
- Analysis of Ku70 acetylation levels in the cytoplasm.
- Assessment of Bax and cytochrome c release from mitochondria.
Main Results:
- Histone deacetylase inhibitor treatment led to increased acetylation of Ku70 in the cytoplasm.
- Increased cytoplasmic Ku70 acetylation resulted in the release of Bax.
- Bax release subsequently triggered the release of cytochrome c from mitochondria, initiating apoptosis.
Conclusions:
- The acetylation of Ku70 in the cytoplasm is a key event in HDAC inhibitor-induced apoptosis.
- This pathway, involving Bax and cytochrome c release, provides a mechanistic understanding of HDAC inhibitor efficacy.
- The findings have implications for the clinical development of histone deacetylase inhibitors in cancer treatment.
Related Concept Videos
01:24Caspases
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway