YTHDC2 inhibits HPV-positive cervical cancer growth by suppressing SLC7A11 in a ferroptosis-dependent manner.

Chronic infection with high-risk human papillomavirus (HPV) types increases the risk of developing cervical cancer (CC). Notably, these HPV types are implicated in ~70% of all CC cases. YTH N6-methyladenosine RNA-binding protein C2 (YTHDC2) is an N6-methyladenosine reader associated with several cancers, although its specific function in CC remains poorly understood. The present study aimed to elucidate new functions of YTHDC2 in HPV-positive CC cell proliferation and ferroptosis, mediated by pathways dependent on protein synthesis. A comparative analysis revealed reduced levels of YTHDC2 in HPV-positive CC samples and cell lines compared with those in HPV-negative samples. YTHDC2 overexpression diminished cell viability and proliferation, whereas silencing YTHDC2 enhanced these processes, according to Cell Counting Kit-8 and colony formation assays. Cells overexpressing YTHDC2 exhibited characteristics of ferroptosis, such as apoptosis, reactive oxygen species production and imbalances in several ferroptosis indicators, including solute carrier family 7 member 11 (SLC7A11). A bioluminescent assay using a firefly luciferase construct fused with the SLC7A11 5'-untranslated region (UTR) demonstrated a reduction in luminescence in cells exhibiting enhanced YTHDC2 expression. This indicated that YTHDC2 catalyzes translation initiation via deconvolution of the 5'-UTR of SLC7A11 mRNA. Alterations to the 5'-UTR led to increased luciferase activity. Furthermore, increased SLC7A11 levels mitigated the effects of YTHDC2 overexpression on proliferation and ferroptosis in CC cells. In conclusion, the results of the present study suggest that low expression of the RNA helicase YTHDC2 contributes to CC proliferation and inhibition of ferroptosis by promoting SLC7A11 translation in HPV-positive CC cells.