Restoration of TET2 deficiency inhibits tumor growth in head neck squamous cell carcinoma

BACKGROUND: Tet methylcytosine dioxygenase 2 (TET2) has been increasingly recognized as an important tumor suppressor involved in tumorigenesis. Here, we aimed to explore the expression pattern of TET2, its clinical significance as well as functional roles in head neck squamous cell carcinoma (HNSCC). METHODS: Both mRNA and protein levels of TET2 in primary HNSCC samples were detected via immunohistochemistry and qRT-PCR, respectively. Correlations between TET2 expression with multiple clinicopathological parameters and patient survival were determined. The biological roles of TET2 in HNSCC were assessed via a gain-of-function approach and in 4-nitroquinoline-1-oxide (4NQO)-induced HNSCC model. Restoration of TET2 by chemicals including 5-Aza-2'-deoxycytidine (5-AZA), metformin or Vitamin C (VC) to inhibit tumor growth was determined in vitro and in a xenograft animal model. RESULTS: Reduced TET2 expression was found in a large fraction of HNSCC samples. Downregulated TET2 significantly correlated with larger tumor size, advanced clinical stage and inferior prognosis. Reduced TET2 and 5-hydroxymethylcytosine (5hmC) were observed along with disease progression in the 4NQO-induced HNSCC model. Enforced TET2 overexpression significantly inhibited cell proliferation, migration and enhanced the chemosensitivity of cisplatin in HNSCC cells. Restoration of TET2 following 5-AZA, metformin or VC exposure impaired cell proliferation and migration in vitro. Moreover, VC alone or in synergistic with cisplatin potently inhibited tumor growth in vivo. CONCLUSIONS: Our data reveal that reduced TET2 associates with tumor aggressiveness and reduced survival in HNSCC. Genetic or pharmacological restoration of TET2 might be a viable therapeutic strategy for HNSCC patients with TET2 deficiency.