Low Dose of Trichostatin A Improves Radiation Resistance by Activating Akt/Nrf2-Dependent Antioxidation Pathway in Cancer Cells.

Abstract

Numerous studies have shown that histone deacetylase inhibitors (HDACis) improve cellular acetylation while also enhancing the radiation sensitivity. In this work, however, we confirmed that low-dose trichostatin A (TSA) as a typical HDACi could reduce rather than increase the radiosensitivity of cancer cells, while the cellular acetylation was also increased with TSA-induced epigenetic modification. The surviving fraction of HeLa/HepG2 cells pretreated with 25 nM TSA for 24 h was higher at 1 Gy/2 Gy of γ-ray radiation than that of the cells with the same radiation dose but without TSA pretreatment. To understand the underlying mechanism, we investigated the effect of low-dose TSA on HO-1, SOD and CAT induction and activating Akt together with its downstream Nrf2 signaling pathway. Our results indicated that TSA activated HO-1, SOD and CAT expression by increasing the phosphorylation level of Nrf2 in an Akt-dependent manner. In addition, we also observed that the 25-nM-TSA-pretreated group showed a significant increase in the antioxidant capacity in terms of SOD and CAT activities. Therefore, our results suggest that low-dose TSA can activate the Akt/Nrf2 pathway and upregulate expression of HO-1, SOD and CAT to stimulate the cellular defense mechanism. This work demonstrates that low-dose TSA treatment may activate the adaptation mechanism against the oxidative stress induced by ionizing radiation, and application of HDACi treatment should be undertaken with caution to avoid its possible radioresistance in radiotherapy.

• Authors: Fengqiu Zhang, Changsheng Shao, Zhu Chen, Yalin Li, Xumiao Jing, Qing Huang
• Journal: Radiation research (Radiat Res) Vol. 195 Issue 4 Pg. 366-377 (04 01 2021) ISSN: 1938-5404 [Electronic] United States
• PMID: 33513620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 by Radiation Research Society. All rights of reproduction in any form reserved.

Chemical References

• Antioxidants
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• trichostatin A
• Proto-Oncogene Proteins c-akt

Topics

• Antioxidants (pharmacology)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Hep G2 Cells
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• NF-E2-Related Factor 2 (genetics)
• Neoplasms (drug therapy, genetics, pathology, radiotherapy)
• Oxidative Stress (drug effects)
• Proto-Oncogene Proteins c-akt (genetics)
• Radiation Tolerance (drug effects, genetics)
• Signal Transduction (drug effects)