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Published on: December 21, 2019
YTHDC2 inhibits HPV-positive cervical cancer growth by suppressing SLC7A11 in a ferroptosis-dependent manner
Li Ren1, Junjun Zhang1, Jinjin Yang1
1Department of Gynecology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.
Abstract:
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.
Insights
Low levels of YTHDC2 promote cervical cancer (CC) growth by enhancing protein synthesis of SLC7A11, inhibiting ferroptosis in human papillomavirus (HPV)-positive CC cells.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- High-risk human papillomavirus (HPV) infection is a primary cause of cervical cancer (CC).
- YTH N6-methyladenosine RNA-binding protein C2 (YTHDC2) is an RNA-binding protein implicated in various cancers, but its role in CC is unclear.
- Understanding YTHDC2's function in HPV-positive CC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of YTHDC2 in HPV-positive cervical cancer cell proliferation and ferroptosis.
- To elucidate the molecular mechanisms underlying YTHDC2's function, particularly its regulation of protein synthesis.
- To determine the relationship between YTHDC2, solute carrier family 7 member 11 (SLC7A11), and ferroptosis in CC.
Main Methods:
- Comparative analysis of YTHDC2 expression in HPV-positive versus HPV-negative CC samples and cell lines.
- Cell viability and proliferation assays (Cell Counting Kit-8, colony formation) following YTHDC2 overexpression or silencing.
- Assessment of ferroptosis markers (apoptosis, reactive oxygen species, SLC7A11 levels).
- Bioluminescent assays using luciferase constructs to analyze SLC7A11 5'-untranslated region (UTR) activity and YTHDC2's effect on translation initiation.
Main Results:
- YTHDC2 expression was significantly reduced in HPV-positive CC samples and cell lines.
- YTHDC2 overexpression inhibited CC cell viability and proliferation, while silencing YTHDC2 enhanced these processes.
- Overexpression of YTHDC2 induced ferroptosis characteristics and reduced SLC7A11 translation via its 5'-UTR.
- Increased SLC7A11 levels partially reversed the effects of YTHDC2 on proliferation and ferroptosis.
Conclusions:
- Reduced YTHDC2 expression in HPV-positive CC promotes cancer cell proliferation and inhibits ferroptosis.
- YTHDC2 regulates CC progression by controlling SLC7A11 translation initiation.
- Targeting YTHDC2 or modulating SLC7A11 levels may offer therapeutic strategies for HPV-positive cervical cancer.
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