Date of Award
2025
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmacology
First Advisor
Frances E. Carr
Abstract
Cancer progression commonly involves the breakdown of transcriptional and epigenetic programs that normally maintain a differentiated cell type, thus allowing tumor cells to acquire stem cell-like properties. This dedifferentiation process is pronounced in aggressive malignancies such as anaplastic thyroid cancer (ATC), a rare but highly lethal type of thyroid cancer with no enduring effective treatments. The dedifferentiation process in ATC is driven by both genetic mutations and widespread epigenetic dysregulation. Alterations in chromatin-modifying mechanisms result in the loss of epithelial cell identity through the silencing of key transcription factors that are involved in maintenance of differentiation-associated gene expression. Identifying and exploiting these pathways hold promise for therapeutic targets in the treatment of ATC.
Lysine-specific demethylase 1 (LSD1) is an epigenetic regulator implicated in the silencing of differentiation programs in various cancers and solid tumors. LSD1 regulates transcription through the demethylation of mono- or di-methylated lysine residues on histone tails (H3K4me1/2 and H3K9me1/2) or through protein-protein interactions with repressor complexes such as CoREST and NuRD. Our prior work indicated that LSD1 is coregulator of thyroid hormone receptor beta (TRβ), a known tumor suppressor, raising the possibility that LSD1 is involved in modulating tumor progression. Preliminary data demonstrates that pharmacological inhibition or genetic knockdown of LSD1 attenuates the malignant phenotype of ATC cells. Thus, we hypothesize that LSD1 is required for normal cellular function in nonmalignant thyroid cells but maintains a dedifferentiated and transcriptionally repressed state in ATC cells. Furthermore, we propose that inhibition of LSD1 can reprogram transcription to support the redifferentiation of ATC cells to a less malignant cellular state.
Through integrating genomic and epigenomic analyses, we investigated the consequences of LSD1 catalytic inhibition using the small molecule SP2509 in order to understand the molecular mechanisms of LSD1-mediated demethylation in both normal epithelial and ATC cells. Our results support a cancer cell context-dependent shift in the LSD1-mediated transcriptome and additional LSD1-conserved mechanisms of transcription factor regulation. These findings will inform the broader therapeutic relevance of targeting LSD1 in thyroid cancer and aid in our understanding of epigenetic mechanisms that are linked to driving cancer progression in both normal epithelial and anaplastic thyroid cancer cells.
Language
en
Number of Pages
61 p.
Recommended Citation
Boisoneau, Jaime, "Transcriptional and Epigenetic Effects of LSD1 Inhibition in Normal Epithelial Thyroid Cells and Anaplastic Thyroid Cancer Cells." (2025). Graduate College Dissertations and Theses. 2127.
https://scholarworks.uvm.edu/graddis/2127