FTO-mediated demethylation of MTUS1/ATIP1 promotes tumor progression in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) has been recognized as the seventh most prevalent malignant tumor globally. It is a malignant neoplasm that arises from the mucosal epithelium of head and neck region. In our previous research, we have demonstrated that MTUS1/ATIP1 exhibits anti-cancer properties in HNSCC. Nevertheless, the underlying mechanism responsible for the reduction of MTUS1/ATIP1 expression has not been investigated.

HNSCC and adjacent normal tissues were collected and examined using m⁶A MeRIP-seq, qRT-PCR, and IHC to investigate the relationship between MTUS1/ATIP1 and FTO. MeRIP-qPCR, m⁶A dot blot, RNA and protein stability assays, and RNC-qRT-PCR were employed to elucidate the mechanism by which FTO mediates demethylation of MTUS1/ATIP1 in HNSCC. Functional assays, subcutaneous tumorigenesis, and in situ tongue cancer models were conducted to assess the impact of the FTO-MTUS1/ATIP1 pathway on proliferative capacity of HNSCC tumors.

FTO was observed to be markedly upregulated and showed a negative correlation with MTUS1/ATIP1 expression in HNSCC. FTO was responsible for mediating m⁶A demethylation in the 3’UTR of MTUS1/ATIP1, leading to its degradation. Additionally, silencing MTUS1/ATIP1 successfully reversed the tumor-promoting effects on HNSCC triggered by FTO in in vitro and in vivo.

Our research elucidated the functional importance of FTO-mediated m⁶A demethylation of MTUS1/ATIP1, suggesting that targeting the FTO-MTUS1/ATIP1 axis could be a prospective novel approach for treating HNSCC.