FOXF2 suppressed esophageal squamous cell carcinoma by reducing M2 TAMs via modulating RNF144A-FTO axis

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers because of its high invasiveness and low survival. Tumor-associated macrophages (TAMs) are closely associated with the tumor cell proliferation, metastasis and immunosuppression. As a member of the FOX family, forkhead box F2 (FOXF2) was down-regulated in ESCC. However, its role in ESCC and TAMs, as well as the underlying mechanism, remains unclear. We found that differentially expressed genes (DEGs) in ESCC were enriched in proliferation, migration, macrophage and cancer pathways. Among these DEGs, FOXF2 caught our eyes. FOXF2 was down-regulated in ESCC. Overexpression FOXF2 inhibited the proliferation of ESCC cells and the M2 polarization of TAMs, but silenced FOXF2 reversed these results. Notably, FOXF2 promoted the transcription of ring finger protein 144A (RNF144A), which is an E3 ubiquitin ligase, causing the ubiquitination and degradation of FTO Alpha-Ketoglutarate Dependent Dioxygenase (FTO), an N6-methyladenosine (m⁶A) demethylase. Furthermore, overexpression of FTO abolished the effects of FOXF2 on TAM polarization. In conclusion, FOXF2 alleviates ESCC via promoting the transcription of RNF144A which results in the ubiquitylation and degradation of FTO. Targeting FOXF2/RNF144A/FOT axis might be a possible strategy for the treatment of ESCC.