Indeed, histone 3 is acetylated following loss of NFκB, resulting in decondensation of tumor chromatin and sensitization of head and neck tumors to chemotherapy. This indicates that the effect of NFκB on chromatin

organization directly influences tumor response to therapy. As proof of concept, administration of HDAC inhibitors recapitulate the effects selleck product of NFκB targeted inhibition by promoting chromatin decondensation and sensitizing tumor cells to chemotherapy, resulting in increased sensitivity of tumor cells to chemotherapy (Figure ​(Figure44). Figure 4 Data from Almeida et al proposing the mechanism for nuclear factor kappa-light-chain-enhancer of activated B cells driven resistance to chemotherapy in head and neck squamous cell carcinoma. Chromatin undergo normal compaction and decondensation through … In addition to chemoresistance, activation of NFκB signaling increases the number of tumor spheres, indicating a broader role of NFκB as an epigenetic switch in CSCs. Notably, NFκB signaling is required for the development of tumor spheres in breast, cervical and head and neck cancers[218] (Almeida and Castilho, submitted). We established that by controlling tumor histones, we can dynamically regulate the behavior and number of HNSCC and its CSCs[151]. Epigenetic

signals may play a major role in stem cell control through deacetylation of histones, which promotes chromatin condensation and reactivation of stem cell-like transcription programs[34]. Aligned with previous reports[219-221], we showed that HNSCC tumor cell lines have a subpopulation of CSC, as detected by elevated ALDH activity, and clonogenic potential[151]. This subpopulation of CSCs is highly tumorigenic and can self-renew, as observed

by serial transplantation assays[37]. By inhibiting HDAC and inducing acetylation of tumor histones, we found that CSCs lose their “stemness”, as evidenced by a reduction in ALDH+ cells and progressive disruption of tumor spheres. These findings indicate that HDAC inhibition disrupts the physiological requirements for CSC maintenance. Indeed, chromatin acetylation induces cellular differentiation and restricts cellular transformation[207,208]. Altogether, HNSCC behavior appears dependent on dynamic changes in chromatin organization GSK-3 and subsequent gene transcription. Unlike stable DNA modifications mediated by methylation, acetylation of histones dynamically alters gene expression, thereby influencing tumor behavior following changes in the microenvironment as observed during administration of secreted factor from endothelial cells[151] and expression of tumor aggressiveness markers[222-225]. CONCLUSION The role of epigenetic modifications in HNSCC warrants further investigation. Compared to histone modifications, the role of DNA methylation in regulating gene expression is better characterized.