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RNA sequencing of Cal33 and SAS head and neck squamous cell carcinoma cell lines treated with GSK-J1 and radiation

ABSTRACT: 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 treat-ment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) pheno-type. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epi-genetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. 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 in-volved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensi-tizing and CSC-targeting potential. Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 tri-methylation, 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. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255896 | GEO | 2024/02/20

REPOSITORIES: GEO

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Project description: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 treat-ment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) pheno-type. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epi-genetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. 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 in-volved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensi-tizing and CSC-targeting potential. Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 tri-methylation, 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. 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.

Project description:A large body of evidence has demonstrated that many human tumors are maintained by a small cell population called cancer stem cells (CSCs) or tumor progenitors, which are responsible for tumor formation, therapy resistance and metastasis. We found that ionizing radiation treatment enriches for the CSC phenotype and properties by preferential survival and expansion of tumor progenitor cells. Our studies revealed that aldehyde dehydrogenase (ALDH) activity is indicative of prostate tumor progenitor cells with increased chemo- and radioresistance, enhanced migratory potential, improved DNA- double strand break repair and activation of the signaling pathways, which promote self-renewal and epithelial-mesenchymal transition. We found that X-ray irradiation can convert the bulk tumor cells to more clonogenic and radioresistant population positive for expression of CSC markers. For the first time we showed that irradiation increases histone H3K4 and H3K36 methylation in prostate cancer cells, thereby reactivating transcription of epigenetically silenced target genes. We showed that radioresistant tumor progenitor population undergoes a phenotypical switching during the course of irradiation, suggesting that controlling the phenotypical and functional properties of CSCs during radiation therapy is ultimative for the optimization of treatment strategies. Our studies have shown that CSC markers may be beneficial in prediction of tumor radiocurability, and combination of irradiation with therapies directed against CSCs can be a useful strategy to improve cancer treatment. To identify potential biomarkers associated with CSC population in these xenograft tumors, we performed whole genome gene expression profiling of the xenograft tumors treated with NVP-BEZ235, which eliminates prostate cancer progenitor populations or with Taxotere, which targets the bulk tumor cells as compared with vehicle-treated control mice. Treatment with either vehicle, Taxotere, NVP-BEZ235, or a combination of these two. There are no replicates

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RNA sequencing of Cal33 and SAS head and neck squamous cell carcinoma cell lines treated with GSK-J1 and radiation

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