SAT-251 - Epigenetic Mechanisms Underlying Trβ-Driven Transcriptional Reprogramming in Anaplastic Thyroid Cancer.

Thyroid hormones and their cognate nuclear thyroid hormone receptors (TRs) are master regulators of chromatin structure that coordinate gene regulatory programs governing cell identity, metabolism, and homeostasis. Compelling evidence indicates that the thyroid hormone receptor beta (TRβ) is a tumor suppressor in anaplastic thyroid cancer (ATC), a rare but lethal disease with no enduring effective treatments. Our prior cell-based and animal studies reveal that activation of TRβ induces apoptosis, reduces the aggressive phenotype, decreases stem-cell populations, and slows tumor growth through suppression of pro-tumorigenic transcriptional networks. However, the underlying chromatin dynamics and epigenetic landscape that shape the TRβ gene regulatory network has yet to be defined in high resolution.

To systematically investigate these mechanisms, we stably transduced ATC cell line 8505c with an inducible expression system encoding HA-tagged wild-type (WT) TRβ, a DNA-binding domain mutant (GS) TRβ, and an empty vector (EV) control. Induction of WT-TRβ, but not GS-TRβ, recapitulated the anti-proliferative phenotype, demonstrating that transcription factor activity is required for tumor suppression. Our transcriptomic analysis reveals growth suppression pathways that are altered by inducing TRβ expression in this model are further amplified upon addition of a thyromimetic ligand, GC-1. To determine the mechanisms driving this transcriptional response, we performed integrated bioinformatics analyses to identify upstream regulators, binding partners, and patterns of differential chromatin accessibility. Together, these data directly link chromatin state to TRβ transcriptional activity and provide mechanistic insight into how TRβ promotes cellular differentiation and attenuates malignant progression in ATC.

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