DOT1L Epigenetically Induces the Expression Level of FoxM1 through H3K79me2 and Affects the Malignant Behaviors of Head and Neck Squamous Cell Carcinoma Cells

Abstract

DOT1-like histone lysine methyltransferase (DOT1L) has been revealed to be highly correlated with progression of diverse types of cancer, while its role in head and neck squamous cell carcinoma (HNSCC) has still remained elusive. In this study, it was found that DOT1L was highly expressed in HNSCC tissues and cell lines, and its high expression level was closely associated with poor prognosis, tumor differentiation, T stage, and pathological stage of HNSCC patients. With the introduction of DOT1L inhibitors, SGC 0946, DOT1L inhibition significantly suppressed proliferation, migration, and invasion of HNSCC cells, while increased their apoptosis rate. To investigate the fundamental mechanism, we predicted that the expression level of Forkhead Box M1 (FoxM1) was positively correlated with DOT1L, and it was found that the expression level of FoxM1 was upregulated in HNSCC tissues and cell lines. Importantly, DOT1L activated FoxM1 through H3K79me2, and inhibition of DOT1L repressed the malignant behaviors of HNSC cells, which could be rescued by FoxM1 overexpression. Taken together, the results suggested that DOT1L could epigenetically induce the expression level of FoxM1 through H3K79me2 and affected the malignant behaviors of HNSCC cells, which could provide novel outcomes for the therapy of HNSC.