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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.