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Updated: May 26, 2025

Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
N6-methyladenosine-mediated EIF3H promotes anaplastic thyroid cancer progression and ferroptosis resistance by
Zeyu Zhang1, Di Zhou1, Xiangyuan Qiu1
1Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
Abstract:
Anaplastic thyroid cancer (ATC) patients suffer from a poor prognosis with very limited treatment options. The accumulation of β-catenin and the activation of downstream signaling is one of the main events in ATC, while the role of JAMM family in ATC remains unknown. In this study, we aimed to identify a new deubiquitinating enzyme regulating β-catenin in ATC. We found that EIF3H was positively correlated with β-catenin, and the knockdown of EIF3H deactivated the Wnt/β-catenin signaling pathway in ATC. Further exploration revealed that EIF3H interacted with, deubiquitylated, and stabilized β-catenin by acting as a deubiquitinating enzyme. Mechanistically, EIF3H removed the K48-linked ubiquitin chain on β-catenin by binding the N tails of β-catenin. The knockdown of EIF3H could inhibit ATC cell proliferation, invasion, and ferroptosis resistance by regulating β-catenin. In addition, the dysregulation of EIF3H was associated with m6A modification in the 3'UTR and a m6A reader, IGF2BP2. In summary, the EIF3H/β-catenin axis promotes ATC progression and ferroptosis resistance by activating the Wnt/β-catenin signaling pathway. The EIF3H/β-catenin axis may serve as a potential diagnostic marker and a therapeutic target in ATC.
Insights
EIF3H deubiquitylates and stabilizes beta-catenin, promoting anaplastic thyroid cancer (ATC) progression and ferroptosis resistance. Targeting the EIF3H/beta-catenin axis offers a potential therapeutic strategy for ATC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Anaplastic thyroid cancer (ATC) has a poor prognosis and limited treatment options.
- The Wnt/beta-catenin pathway is crucial in ATC, but regulatory mechanisms are not fully understood.
- The role of the JAMM family of deubiquitinating enzymes in ATC is unknown.
Purpose of the Study:
- To identify a novel deubiquitinating enzyme that regulates beta-catenin in ATC.
- To elucidate the mechanism by which this enzyme affects beta-catenin stability and Wnt/beta-catenin signaling.
- To investigate the therapeutic potential of targeting this enzyme in ATC.
Main Methods:
- Correlation analysis between EIF3H and beta-catenin expression in ATC.
- EIF3H knockdown experiments to assess effects on Wnt/beta-catenin signaling.
- Biochemical assays to confirm interaction, deubiquitylation, and stabilization of beta-catenin by EIF3H.
- Assessment of EIF3H's impact on ATC cell proliferation, invasion, and ferroptosis resistance.
- Investigation of EIF3H's association with m6A modification and IGF2BP2.
Main Results:
- EIF3H expression positively correlates with beta-catenin levels in ATC.
- EIF3H knockdown inhibits the Wnt/beta-catenin pathway, reducing ATC cell proliferation and invasion.
- EIF3H directly deubiquitylates and stabilizes beta-catenin by removing K48-linked ubiquitin chains.
- EIF3H knockdown enhances ferroptosis sensitivity in ATC cells.
- EIF3H dysregulation is linked to m6A modification and the m6A reader IGF2BP2.
Conclusions:
- The EIF3H/beta-catenin axis promotes ATC progression and ferroptosis resistance via Wnt/beta-catenin signaling activation.
- EIF3H acts as a deubiquitinating enzyme targeting beta-catenin.
- The EIF3H/beta-catenin axis presents a potential diagnostic marker and therapeutic target for ATC.
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