5-AZA-2’-deoxycytidine as a potential therapeutic option in the treatment of head and neck squamous cell carcinoma (HNSCC)

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Eadie, Hannah Jessica (2019). 5-AZA-2’-deoxycytidine as a potential therapeutic option in the treatment of head and neck squamous cell carcinoma (HNSCC). University of Birmingham. Ph.D.

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. Epigenetic mechanisms including changes in DNA methylation (5mC) and hydroxymethylation (5hmC) are major contributors to HNSCC progression and can be altered by the use of epigenetic therapies such as the DNA demethylating agent, 5-aza-2’-deoxycytidine (DAC). Here, the potential use of DAC in the treatment of HNSCC was investigated and a subset of HNSCC cell lines determined to respond to nanomolar concentrations of the drug. Furthermore, the efficacy of DAC was significantly increased by co-treatment with the common analgesic, paracetamol, providing an appealing new therapeutic option.

Genome-wide sequencing methods were used to compare the distribution of 5mC and 5hmC between normal oral keratinocytes and an HNSCC cell line and investigate how this is altered by DAC. In addition to causing global DNA demethylation, DAC partially restores 5mC and 5hmC patterns to those of normal oral keratinocytes. In normal cells, 5mC and 5hmC mark clusters of Alu elements in gene rich regions; this is dramatically reduced in HNSCC. Treatment with DAC restores DNA modifications to Alu elements, leading to repression of Alu RNA. Furthermore, DAC caused demethylation and increased expression of endogenous retroviruses, prompting a viral mimicry response.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):