Epigenetic targeting to overcome radioresistance in head and neck cancer

• Verfasst von: Schniewind, Iñaki [VerfasserIn]
• Verfasst von: Besso, Maria José [VerfasserIn]
• Verfasst von: Klicker, Sebastian [VerfasserIn]
• Verfasst von: Schwarz, Franziska Maria [VerfasserIn]
• Verfasst von: Hadiwikarta, Wahyu Wijaya [VerfasserIn]
• Verfasst von: Richter, Susan [VerfasserIn]
• Verfasst von: Löck, Steffen [VerfasserIn]
• Verfasst von: Linge, Annett [VerfasserIn]
• Verfasst von: Krause, Mechthild [VerfasserIn]
• Verfasst von: Dubrovska, Anna [VerfasserIn]
• Verfasst von: Baumann, Michael [VerfasserIn]
• Verfasst von: Kurth, Ina [VerfasserIn]
• Verfasst von: Peitzsch, Claudia [VerfasserIn]
• Titel: Epigenetic targeting to overcome radioresistance in head and neck cancer
• Verf.angabe: Iñaki Schniewind, Maria José Besso, Sebastian Klicker, Franziska Maria Schwarz, Wahyu Wijaya Hadiwikarta, Susan Richter, Steffen Löck, Annett Linge, Mechthild Krause, Anna Dubrovska, Michael Baumann, Ina Kurth and Claudia Peitzsch
• E-Jahr: 2024
• Jahr: 9 February 2024
• Umfang: 21 S.
• Illustrationen: Illustrationen
• Fussnoten: Titel des special issue: "Cellular plasticity: tumorigenesis and therapy" ; Gesehen am 07.02.2025
• Titel Quelle: Enthalten in: Cancers
• Ort Quelle: Basel : MDPI, 2009
• Jahr Quelle: 2024
• Band/Heft Quelle: 16(2024), 4, special issue, Artikel-ID 730, Seite 1-21
• ISSN Quelle: 2072-6694
• DOI: doi:10.3390/cancers16040730
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cancer stem cells
• Sach-SW: cellular plasticity
• Sach-SW: head and neck cancer
• Sach-SW: histone methylation
• Sach-SW: radioresistance
• K10plus-PPN: 1916692869

Abstract

(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy.