Trichostatin A induces p 53 ‐ dependent endoplasmic reticulum stress in human colon cancer cells

Trichostatin A (TSA) has been demonstrated to exhibit various anticancer effects that influence cell cycle arrest, cell proliferation and apoptosis of cancer cells. A potential association between TSA and endoplasmic reticulum (ER) function has been suggested but its anticancer mechanism involving the induction of ER stress is unknown. p53 has previously been demonstrated to regulate ER function in response to stress but its role involving TSA and ER stress in cancer cells is poorly understood. The current study identified that TSA induced ER stress in wild type (WT) HCT116 human colon cancer cells. Following TSA treatment, the ER stress markers GRP78 and GRP94 significantly increased without hyperacetylation of their promoter regions. The inositol‐requiring enzyme 1 α (IRE1α)/X‐box binding protein 1 (XBP1) pathway was implicated due to an association of phosphorylated IRE1α and spliced XBP1 with ER stress. However, luciferase reporter assay indicated that splicing events were attenuated in HCT116 TP53(‐/‐) cells. Furthermore, cell viability and apoptosis were revealed to depend on p53 during TSA treatment. Cell viability increased and the apoptosis rate decreased in HCT116 TP53(‐/‐) cells compared with WT HCT116 cells undergoing TSA treatment. In conclusion, the current study revealed that TSA may induce ER stress via a p53‐dependent mechanism in colon cancer cells. This provides information that may assist the development of treatments that exploit the anticancer function of TSA. Introduction Trichostatin A (TSA) is a histone deacetylase (HDAC) inhibitor of class I and II HDACs. TSA influences gene expression by interfering with the removal of acetyl groups from histones, thereby altering the balance between DNA transcription factors and chromatin (1). Based on the known medicinal properties of HDAC inhibitors, TSA has been tested as a treatment against various cancer cells with highly expressed HDACs, including colon (2), breast (3) and lung (4) cancer cells. TSA is known to affect the growth, apoptosis, autophagy and/or differentiation processes of these cancer cells. Previous studies have identified a potential association between TSA and endoplasmic reticulum (ER) function (5); however, to the best of our knowledge, an anticancer mechanism involving TSA and ER stress is unknown. To investigate ER stress, dysfunction of the ER and the unfolded protein response was induced under adverse conditions, including metabolic and anaerobic stress, which disrupts the protein‐folding function of the ER. Altered ER homeostasis results in an accumulation of unfolded or misfolded proteins, which ultimately leads to ER stress (6,7). The ER stress response activates cytotoxic mechanisms involving a number of regulatory cytokines associated with the onset of programmed cell death, suggesting this is a possible target in the development of chemotherapeutic agents for inducing cancer cell toxicity (8). As an essential tumor suppressor, the TP53 gene regulates the processes of ER stress, apoptosis, DNA repair, cell cycle and nuclear vesicular trafficking, in the presence of cellular stressors, including hypoxia, DNA damage and oncogene activation (9,10). Previous studies have revealed that p53 is upregulated in response to ER stress and participates in ER stress‐induced apoptosis (11). However, to the best of our knowledge, the role of p53 in cancer cells exposed to TSA and ER stress is not understood. In the current study, the anticancer effect of TSA on ER function was investigated in the HCT116 cell line. It was identified that ER stress was induced by TSA. Additionally, the inositol‐requiring enzyme 1 α (IRE1α)/X‐box binding protein 1 (XBP1) pathway was implicated in wild type (WT) HCT116 cells. Mutation or silencing of TP53 attenuated ER stress. Cell viability increased and the apoptosis rate decreased in HCT116 TP53(‐/‐) cells compared with WT HCT116 cells undergoing TSA treatment. Therefore, the induction Trichostatin A induces p53‐dependent endoplasmic reticulum stress in human colon cancer cells LIMENG DAI1, GANG HE1, KUN ZHANG2, XINGYING GUAN1, YAN WANG1 and BO ZHANG1 Departments of 1Medical Genetics and 2Pathogenic Biology, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, P.R. China Received February 26, 2018; Accepted September 24, 2018 DOI: 10.3892/ol.2018. 9641 Correspondence to: Professor Bo Zhang, Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), 30 Gaotanyan, Chongqing 400038, P.R. China E‐mail: bo_zhang@yahoo.com