.. Figure 3 Data from Giudice et al[151] showing

the impact of histone deacetylases inhibitor on the population of CICs. A: Fluorescence-activated cell sorting of ALDH+ cells demonstrates that HNSCC cell lines have a high number CICs, and that administration of TSA … In summary, histone modifications via methylation, acetylation and deacetylation play a critical role in purchase Ponatinib transcriptional activation and gene expression. Aside from the physiological maintenance of cellular homeostasis, aberrant alterations in histone methylation proteins and/or an imbalance in the HAT/HDAC network results in dysfunctions in cellular processes, such as proliferation, differentiation, DNA repair and apoptosis. Importantly, post-translational histone modification and DNA methylation can have similar patterns in the same cancer type. For example, a study by Piyathilake et al[209] revealed that patterns of global DNA and histone methylation are similar in different human mucosal tissues (e.g., normal, dysplastic and squamous cell carcinoma). Using immunohistochemical analysis, they also found that global DNA methylation and H3 methylation at lysine 4 and lysine 9 are significantly higher in dysplastic lesions and carcinoma cells compared to normal oral epithelium[209]. Therefore, when developing methods and techniques for

identifying epigenetic markers in premalignant cells, we must consider analyzing both global DNA and histone methylation levels concurrently in the progression of cancer. In conclusion, the previously described epigenetic alterations are closely associated with tumorigenesis and malignancy in many types of cancers. As a result, genomic instability affects numerous

intracellular signaling cascades. We will discuss the NFκB signaling pathway in the next section. TUMOR HISTONE MODIFICATIONS: EVIDENCE FOR AN EPIGENETIC MECHANISM RESPONSIBLE FOR ACQUIRED TUMOR RESISTANCE TO THERAPY NFκB is an epigenetic modifier that plays a major role in malignant transformation[210], and this pathway serves as a target for epigenetic drugs[211-213]. We, along with others, have previously reported that constitutive activation of NFκB signaling is often observed in HNSCC, suggesting a common epigenetic mechanism in HNSCC AV-951 biology[214,215]. Indeed, activation of NFκB signaling in HNSCC induced chromatin compaction and acquisition of resistance to chemotherapy[216]. NFκB is active following its translocation to the nucleus, a process that is regulated by the IκB kinase (IKK) complex. IκB proteins are targeted for degradation by phosphorylation, which permits nuclear translocation. Nuclear NFκB binds to target DNA sequences and modulates the expression of target genes involved in immune response, cell growth, and cell survival[217]. Targeted inhibition of NFκB through IKKα and IKKβ silencing resulted in disrupted accumulation of nuclear phospho-p65, increased acetylation of histone 3 and accumulation of BRCA1.