Date of Completion

2023

Document Type

Honors College Thesis

Department

Pharmacology

Thesis Type

Honors College, College of Arts and Science Honors

First Advisor

Frances Carr

Second Advisor

Bryan Ballif

Third Advisor

Princess Rodriguez

Keywords

LSD1, KDM1A, Anaplastic thyroid cancer, Thyroid hormone receptor, sobetirome, GC-1

Abstract

Thyroid cancer is the most common endocrine cancer, with anaplastic thyroid cancer (ATC) being the deadliest form due to its lack of thyroid differentiation and the associated ability to metastasize readily throughout the body. Current treatments can only prolong life by approximately six months following diagnosis. Thyroid hormone receptor β (TRβ) is a ubiquitously expressed ligand-dependent nuclear transcription factor that is known to be expressed at very low levels in ATC. TRβ is activated by the endogenous thyroid hormone T3, but this also activates TRα, which can result in severe cardiac symptoms such as tachycardia if over-activated. Numerous solid tumor studies, including some performed by the Carr lab, have illustrated that TRβ is a tumor suppressor. Sobetirome, or GC-1, is a thyroid hormone mimetic that selectively binds to and activates TRβ. In many other endocrine cancers, a mutation in KDM1A, or the lysine-specific histone demethylase 1A, has been found, resulting in elevated levels of its corresponding protein LSD1 in the tumor. LSD1 is an epigenetic modifier that can alter the expression of genes in the cell, resulting in harmful effects. We have extended previous work performed by the Carr Lab and have shown that treatment with GC-1 induces the differentiation of the 8505C cell line of ATC cells into thyroid cells and an associated decrease in stem cell character. For the first time, we illustrated that the tumor suppressor TRβ and the tumor promoter LSD1 are binding partners in ATC cells, extending previous research performed in normal thyroid cells by the Carr Lab. Finally, we demonstrated that the inhibition of KDM1A through various methods results in the decrease of the stem cell character of the ATC cell line, 8505C. These studies establish the role of KDM1A in ATC and the effects of GC-1, both of which provide the potential for new treatment methods for anaplastic thyroid cancer.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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