Date of Completion

2025

Thesis Type

College of Arts and Science Honors

Department

Biochemistry

First Advisor

Frances Carr

Keywords

Anaplastic thyroid cancer, thyroid hormone receptor, lysine-specific demethylase 1 (LSD1), protein-protein interactions

Abstract

Anaplastic thyroid cancer (ATC) is a highly aggressive form of dedifferentiated thyroid cancer that accounts for approximately 40% of thyroid cancer-related deaths. Thyroid hormone receptor beta (TRβ), a nuclear hormone receptor, has been characterized as a tumor suppressor in thyroid cancers and has decreased levels in ATC relative to normal thyroid. Triiodothyronine (T3), the natural ligand to TRβ and thyroid hormone receptor alpha (TRα), and Sobetirome (GC-1), a selective agonist for TRβ, have been shown to induce redifferentiation of ATC cell lines and inhibit their proliferation and stemness. One potential binding partner of TRβ, lysine-specific demethylase 1 (LSD1), was detected via miniTurbo-bioID analysis in the Carr Lab. This protein is dysregulated in ATC and has been shown to demethylate histone lysine residues, thus controlling gene expression through epigenetic modifications. LSD1 is encoded for by the KDM1A gene, which is mutated in several endocrine cancers and results in a disruption of the ratio of TRβ and LSD1 based on analysis of patient data. We have built off previous research to demonstrate the optimal immunofluorescent visualization of TRβ and LSD1 colocalization signals in normal thyroid and ATC cell lines. Furthermore, we have established the foundation for future quantification of their direct interaction in situ and the impact of TRβ activation and LSD1 inhibition on this interaction. This work furthers our understanding of the dynamic protein complexes that mediate TRβ tumor suppression and the role that LSD1 plays in promoting the aggressive phenotype of ATC. The results of these studies provide context for the development of novel therapeutics for ATC and additional endocrine cancers with few treatment options and poor prognoses.

Download

Share

COinS