Epigenetic Regulation of Head and Neck Squamous Cell Carcinoma Chemoresistance, Invasion, and Metastasis

Development of chemoresistance, invasive growth, and metastasis remain key challenges in head and neck squamous cell carcinoma (HNSCC) therapy. Recent studies revealed that an activated hepatocyte growth factor receptor (MET) is frequently overexpressed and highly associated with HNSCC invasion and metastasis. Also, autophagy, a highly conservative intracellular recycling system, has shown to play a primary role in cancer cells to attenuate cytotoxicity of chemoreagents in many hematopoietic and solid cancers. However, little is known about the epigenetic regulation of the MET signaling pathway or autophagy induction and whether it plays a role in promoting HNSCC invasion and metastasis or development of resistance to therapy. In our study, we found that histone deacetylase 6 (HDAC6) is a key epigenetic regulator of autophagy that promotes chemoresistance in HNSCC against the proteasome inhibitor, Bortezomib. The depletion of HDAC6 inhibited autophagy activation and enhanced Bortezomib-induced apoptosis in HNSCC cells. Mechanistically, we revealed that HDAC6 mediated activation of autophagy by modulating activation of protein kinases such as unc-51 like autophagy activating kinase 1 (ULK1) to promote clearing of large quantities of cytotoxic, unfolded protein aggregates induced by the Bortezomib. In addition, we found histone demethylases KDM6B plays an important role in acquiring cisplatin resistance in HNSCC and in unraveling the mechanism associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Interestingly, we also identified KDM6B as an essential epigenetic regulator of MET-driven HNSCC metastasis. KDM6B was highly expressed in both the growth factor-induced HNSCC cells and in cells overexpressing the oncogenic translocated promoter region MET (TPR-MET). KDM6B knockdown significantly decreased the HNSCC invasion and metastasis by regulating the expression of ETS proto-oncogene 1 (ETS1) and the high mobility group AT-Hook 2 (HMGA2) genes, known as the drivers of metastasis. Mechanistically, KDM6B facilitated the binding of the transcription factor ELK1, a downstream target of c-MET signaling pathway, to the promoters of ETS1 and HMGA2. In conclusion, our study provides insight into the epigenetic regulation of HNSCC chemoresistance, invasion, and metastasis and suggests that HDAC6 and KDM6B could be an important therapeutic target to improve chemotherapeutic efficacy and to decrease the tumor burden of HNSCC patients