PURPOSE: Histone deacetylase inhibitors (HDACi) are actively explored as 
new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To 
reveal new mechanism for combination therapy, we show that HDACi induce cell 
death but simultaneously activate tumor-progressive genes to ruin therapeutic 
efficacy. Combined treatments to target tumorigenesis and HDACi-activated 
metastasis with low toxic modalities could develop new strategies for long-term 
cancer therapy.
EXPERIMENTAL DESIGN: Because metastasis is the major cause of cancer mortality, 
we measured cell migration activity and profiled metastasis-related gene 
expressions in HDACi-treated cancer cells. We developed low toxic combination 
modalities targeting tumorigenesis and HDACi-activated metastasis for 
preclinical therapies in mice.
RESULTS: We showed that cell migration activity was dramatically and dose 
dependently enhanced by various classes of HDACi treatments in 13 of 30 examined 
human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was 
also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs 
and downstream substrates along with upregulated proapoptotic p21. For targeting 
tumorigenesis and metastasis with immediate clinical impact, we showed that new 
modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or 
tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and 
cell migration in vitro but also inhibited tumor growth and metastasis in vivo.
CONCLUSION: Treatments of different structural classes of HDACi simultaneously 
induced cell death and promoted cell migration and metastasis in multiple cancer 
cell types. Suppression of HDACi-induced PKCs leads to development of low toxic 
and long-term therapeutic strategies to potentially treat cancer as a chronic 
disease.