Chromatin Remodeling In Head And Neck Squamous Cell Carcinoma Behavior

Objectives: Histone modifications are known to regulate chromatin structure and gene expression in adult cells and pluripotent stem cells. It has been postulated that histone deacetylation could influence the expression of genes involved in cancer initiation, progression, metastasis, and development of resistance to chemotherapies. Here, we sought to evaluate the influence of histone acetylation over the biology of head and neck squamous cell carcinomas (HNSCC) and their stem cell-like population. Methods: Initially, we checked the status of histone acetylation in a representative set of HNSCC cell lines. Subsequently, to analyze the influence of tumor stroma over HNSCC histone acetylation, we mimicked the tumor microenvironment by using conditioned medium from primary human endothelial cells. Finally, we induced chromatin acetylation in HNSCC cell lines through the administration of the histone deacetylase inhibitor Trichostatin A (TSA) following by the analysis of orospheres formation (cancer stem cell functional assay), along with the levels of stem cells marker ALDH (showed by cell sorting - FACS), tumor proliferation index (Ki-67), and tumor invasion. Results: HNSCC cell lines showed lower levels of histone acetylation. Conditioned medium from human endothelial cells induced chromatin acetylation and increased aggressivity of HNSCC cell lines (enhanced BMI-1 and vimentin levels). HNSCC cell lines are capable of retaining a sub-population of pluripotent tumor cells. Interestingly, TSA treatment resulted in significant decrease of the cancer stem cell sub-population by disrupting the orospheres and reducing the levels of ALDH. Also, TSA induced Epithelial to Mesenchymal Transition (EMT) observed by the upregulation of vimentin and the induction of a fusiform phenotype along with augmented tumor invasion and the levels of BMI-1. Conclusions: Chromatin organization is involved in the modulation of cancer stem cell-like cells where high levels of histone acetylation intensifies the aggressive behavior of HNSCC cells.