Thyroid Hormone Receptor β Suppression of RUNX2 Is Mediated by Brahma-Related Gene 1-Dependent Chromatin Remodeling

• Published in: Endocrinology (Philadelphia) 2018-06, Vol.159 (6), p.2484-2494
• Main Authors: Gillis, Noelle E, Taber, Thomas H, Bolf, Eric L, Beaudet, Caitlin M, Tomczak, Jennifer A, White, Jeffrey H, Stein, Janet L, Stein, Gary S, Lian, Jane B, Frietze, Seth, Carr, Frances E
• Format: Article
• Language: English
• Subjects: Carcinogenesis - genetics; Cells, Cultured; Chromatin Assembly and Disassembly - genetics; Core Binding Factor Alpha 1 Subunit - genetics; DNA Helicases - physiology; Down-Regulation - genetics; Gene Expression Regulation; HEK293 Cells; Humans; Nuclear Proteins - physiology; Thyroid Hormone Receptors beta - physiology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Transcription Factors - physiology
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2018-00128

Thyroid hormone receptor β (TRβ) suppresses tumor growth through regulation of gene expression, yet the associated TRβ-mediated changes in chromatin assembly are not known. The chromatin ATPase brahma-related gene 1 (BRG1; SMARCA4), a key component of chromatin-remodeling complexes, is altered in many cancers, but its role in thyroid tumorigenesis and TRβ-mediated gene expression is unknown. We previously identified the oncogene runt-related transcription factor 2 (RUNX2) as a repressive target of TRβ. Here, we report differential expression of BRG1 in nonmalignant and malignant thyroid cells concordant with TRβ. BRG1 and TRβ have similar nuclear distribution patterns and significant colocalization. BRG1 interacts with TRβ, and together, they are part of the regulatory complex at the RUNX2 promoter. Loss of BRG1 increases RUNX2 levels, whereas reintroduction of TRβ and BRG1 synergistically decreases RUNX2 expression. RUNX2 promoter accessibility corresponded to RUNX2 expression levels. Inhibition of BRG1 activity increased accessibility of the RUNX2 promoter and corresponding expression. Our results reveal a mechanism of TRβ repression of oncogenic gene expression: TRβ recruitment of BRG1 induces chromatin compaction and diminishes RUNX2 expression. Therefore, BRG1-mediated chromatin remodeling may be obligatory for TRβ transcriptional repression and tumor suppressor function in thyroid tumorigenesis.