It is likely that VE-821 response to TSA in vivo involves a complex set of host-dependent and tumor-dependent interactions that require further elucidation. Nonetheless, it is important to emphasize that tumor-cell expression of IRF-8 was crucial for therapeutic response to HDACi. We also showed that TSA in combination with IFN-c boosted IRF-8 expression. Similar results were observed with DP, suggesting that modulation of IRF-8 expression was not limited to TSA. Moreover, similar results with TSA were observed in a PF-04217903 c-Met inhibitor second tumor cell model, suggesting that the effects of HDACi on IRF-8 expression were not tumor model-specific. These results support the notion that HDACi, potentially in concert with certain innate or adaptive inflammatory signals, can enhance sensitivity to apoptosis in otherwise refractory or resistant tumor subpopulations. The ability to do so was illustrated using a highly aggressive CMS4 subline, which became more responsive to IRF-8 induction following exposure to TSA or DP alone or in combination with IFN-c. Although it remains to be fully investigated why the two cell lines varied in their response to IRF-8 induction, these data nonetheless provide evidence that IRF-8 is a key component for response to HDACi. Future studies will also determine whether the epigenetic profile of the IRF-8 promoter is different in CMS4 vs. CMS4-met.sel cells, which may help to explain in part their differential responsiveness of IRF-8 induction to TSA treatment. To further demonstrate the importance of IRF-8 in this model, we examined the effects of TSA on IRF-8 promoter activity using a reporter assay. It is important to note that this IRF-8 promoter construct contains the endogenous DNA sequence without any hypermethylation or HDAC sites. Thus, these experiments were designed not only to substantiate the effect of TSA on IRF-8 expression, but also to determine whether the effect of TSA on IRF-8 promoter activity was HDAC-dependent. We hypothesized that if the acetylation status of IRF-8 matters for response to TSA, then an IRF-8 promoter sequence lacking HDAC sites would be unresponsive to TSA treatment. We found that TSA alone and more so in combination with IFN-c increased IRF-8 promoter activity in both parental and aggressive CMS4 cells. For both cell lines after TSA treatment, the IRF-8 patterns seen at the promoter level paralleled the IRF-8 patterns observed at the mRNA level. It is interesting to note, however, that since the exogenous promoter fragment did not contain deacetylation sites, these data suggest that TSA could modulate IRF-8 transcription via mechanisms not necessarily related to HDAC inhibition at the promoter level. We next examined the integrity of events upstream of IRF-8, mainly STAT1 as it is known to be essential for IFN-c-inducible gene regulation, including IRF-8. Phosphorylation of STAT1 plays an important role in regulating IFN-c-mediated gene induction.