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Updated: Jul 2, 2025
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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
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Epigenetic Targeting to Overcome Radioresistance in Head and Neck Cancer
Iñaki Schniewind1,2,3, Maria José Besso4, Sebastian Klicker1
1National Center for Tumor Diseases (NCT), Faculty of Medicine, University Hospital Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany.
Cancers
|February 24, 2024
Summary
Targeting epigenetic regulators like UTX (KDM6A) can prevent radiation resistance in head and neck cancer. This approach may sensitize cancer stem cells (CSCs) to radiotherapy, improving patient outcomes.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Stem Cell Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) radiation sensitivity depends on cancer stem cells (CSCs) with stem-like features.
- Irradiation can enrich for radioresistant CSCs, driven by dynamic cellular plasticity.
- Epigenetic mechanisms, including DNA and histone methylation, regulate gene expression and cellular plasticity.
Purpose of the Study:
- To investigate epigenetic alterations driving irradiation-induced plasticity in HNSCC.
- To identify epigenetic targets that prevent radioresistance and sensitize HNSCC to radiotherapy.
- To evaluate the prognostic and therapeutic potential of targeting histone demethylases.
Main Methods:
- Comparative analysis of DNA methylome and metabolite profiles in radioresistant vs. parental HNSCC cell lines and CSCs.
- Screening of epigenetic enzyme inhibitors in combination with irradiation.
- Assays for clonogenic survival, sphere formation, and DNA repair capacity.
- Analysis of KDM6A and KDM6B expression in patient HNSCC tissue samples.
Main Results:
- The histone demethylase inhibitor GSK-J1, targeting UTX (KDM6A) and JMJD3 (KDM6B), increased H3K27 trimethylation and gene silencing.
- siRNA-mediated knockdown of KDM6A and KDM6B sensitized HNSCC cell lines to irradiation.
- High KDM6A expression correlated with improved locoregional control in HNSCC patients treated with radio/chemotherapy.
- High KDM6B expression was associated with reduced overall survival.
Conclusions:
- Epigenetic alterations play a crucial role in HNSCC radioresistance and cellular plasticity.
- UTX (KDM6A) is identified as a potential prognostic and therapeutic target for HNSCC patients undergoing radiotherapy.
- Targeting epigenetic mechanisms offers a promising strategy to overcome radioresistance in HNSCC.
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