Epigenomic Modulators and Thyroid Hormone Receptor Beta Agonists: A New Paradigm for Tumor Suppression in Thyroid Cancer

The transcription factor thyroid hormone receptor beta (TRβ), a recognized tumor suppressor, interacts with chromatin modifying protein complexes to modulate the transcriptome and induce a tumor suppression gene regulatory network. Recent studies have linked poorly differentiated and anaplastic thyroid cancers to aberrant epigenomic signaling, chromatin accessibility, and gene expression. As no enduring treatments are available for these aggressive thyroid cancers and treatment resistant disease, unveiling the epigenomic co-regulatory proteins mediating TRβ signaling will advance the understanding of the molecular mechanisms of TRβ action to block tumor progression and reveal potential novel therapeutic targets. In this review, we summarize novel findings on the epigenomic landscape in the context of TRβ in thyroid malignancy, including the identification of previously unrecognized TRβ interactors and the mapping of nine distinct functional protein communities that constitute the TRβ interactome in thyroid cells. We also explore how targeting TRβ interactors using existing epigenetic enzyme inhibitors—such as HDAC, LSD1, and BET inhibitors—in combination with TRβ agonists, may work synergistically to reprogram tumor epigenetics and suppress oncogenic transcriptional programs.