Suberoylanilide hydroxamic acid induces thioredoxin1-mediated apoptosis in lung cancer cells via up-regulation of miR-129-5p.

Histone deacetylase (HDAC) inhibitors, especially suberoylanilide hydroxamic acid (SAHA) induce apoptosis in various cancer cells. Here, we investigated the effect of SAHA on apoptosis in lung cancer cells and addressed the role of reactive oxygen species (ROS), glutathione (GSH), and thioredoxin1 (Trx1) levels in this process. We also identified the miRNAs that down-regulate Trx1 expression at RNA level and thereby influence apoptotic cell death of SAHA increased intracellular ROS levels and promoted apoptotic cell death in cancerous cells but not in non-cancerous normal lung cells. Likewise, SAHA induced GSH depletion specifically in cancerous cells. While N-acetyl cysteine (NAC) reduced ROS level and reversed the effect of SAHA on cell death, L-buthionine sulfoximine (BSO) further enhanced GSH depletion, and promoted cell death. SAHA decreased the mRNA and protein levels of Trx1 in lung cancer cells. Knockdown/suppression of Trx1 intensified apoptosis in SAHA-treated lung cancer cells whereas overexpression of Trx1 prevented the cell death in these cells. SAHA up-regulated the level of miR-129-5p, which binds to 3' untranslated region (3'UTR) of Trx1 and down-regulates Trx1 expression. Down-regulation of Trx1 led to activation of apoptosis-signal regulating kinase (ASK), which induced apoptotic cell death by triggering ASK-JNK or ASK-p38 kinase pathway. In conclusion, changes in ROS and GSH levels in SAHA-treated lung cancer cells partially co-related with cell death. SAHA induced apoptosis via the down-regulation of Trx1, which was regulated by miR-129-5p.