Melatonin (N-acetyl-5-methoxytryptamine) has differentiated the effects on apoptosis in normal and cancer cells. The mechanisms that account for the opposite effects on these cells are not adequately understood. In this study, we investigated the combined effect of melatonin and thapsigargin (TG) on apoptosis of renal cancer cells. Cotreatment with melatonin (1mm) and TG (50nm) induced approximately 10-fold expression levels of CCAAT-enhancer-binding proteins homologous protein (CHOP) compared with that of TG (50nm) alone. Downregulation of CHOP expression using small interfering RNAs markedly attenuated melatonin plus TG-mediated apoptosis. In addition, cotreatment with TG- and melatonin-induced CHOP upregulation likely relates to melatonin's antioxidant capacity because we proved that this CHOP upregulation is melatonin receptor independent. Our results collectively demonstrate that the upregulation of CHOP contributes to the enhancing effect of melatonin plus TG on apoptosis in cancer cells.
High mobility group box 1 (
HMGB
1) has been proposed as crucial in the pathogenesis of many diseases including sepsis. Acetylation of
HMGB
1 prevents its entry into the nucleus and leads to its secretion from the cell where it can trigger inflammation. We hypothesized that histone deacetylase 4 (
HDAC
4) controls the acetylation of
HMGB
1 in lipopolysaccharide (
LPS
)‐stimulated
RAW
264.7 cells via the janus kinase (
JAK
)/signal transducer and activator of transcription (
STAT
) pathway. The results showed that
LPS
treatment promoted the degradation of
HDAC
4 in a proteasome‐dependent manner, which led to
HMGB
1 acetylation. In
LPS
‐activated
RAW
264.7 cells, treatment with
TAK
‐242 (a toll like receptor 4 inhibitor) and pyridone 6 (a
JAK
inhibitor) significantly inhibited
HDAC
4 degradation and acetylation of
HMGB
1, and thus prevented secretion of
HMGB
1. Decreased phosphorylation of
STAT
1 was also observed. Interestingly,
HDAC
4 overexpression significantly prevented the acetylation and secretion of
HMGB
1 in both
RAW
264.7 cells and isolated murine peritoneal macrophages. We conclude that
HDAC
4 might be a useful target for the treatment of sepsis.
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