Regulation of the THRA gene, encoding the thyroid hormone nuclear receptor TR alpha 1, in intestinal lesions

Author(s)

Giolito, Maria Virginia ; La Rosa, Theo ; Farhat, Diana ; Bodoirat, Serguei ; Guardia, Gabriela D. A. ; Domon-Dell, Claire ; Galante, Pedro A. F. ; Freund, Jean-Noel ; Plateroti, Michelina

• Document type: Journal article
• Source: MOLECULAR ONCOLOGY; v. 16, n. 22, p. 19-pg., 2022-10-10.

Abstract

The THRA gene, encoding the thyroid hormone nuclear receptor TR alpha 1, is expressed in an increasing gradient at the bottom of intestinal crypts, overlapping with high Wnt and Notch activities. Importantly, THRA is upregulated in colorectal cancers, particularly in the high-Wnt molecular subtype. The basis of this specific and/or altered expression pattern has remained unknown. To define the mechanisms controlling THRA transcription and TR alpha 1 expression, we used multiple in vitro and ex vivo approaches. Promoter analysis demonstrated that transcription factors important for crypt homeostasis and altered in colorectal cancers, such as transcription factor 7-like 2 (TCF7L2; Wnt pathway), recombining binding protein suppressor of hairless (RBPJ; Notch pathway), and homeobox protein CDX2 (epithelial cell identity), modulate THRA activity. Specifically, although TCF7L2 and CDX2 stimulated THRA, RBPJ induced its repression. In-depth analysis of the Wnt-dependent increase showed direct regulation of the THRA promoter in cells and of TR alpha 1 expression in murine enteroids. Given our previous results on the control of the Wnt pathway by TR alpha 1, our new results unveil a complex regulatory loop and synergy between these endocrine and epithelial-cell-intrinsic signals. Our work describes, for the first time, the regulation of the THRA gene in specific cell and tumor contexts. (AU)

• FAPESP's process: 17/19541-2 - Impact of RNA binding proteins on abnormal regulation of splicing in glioblastoma
• Grantee: Gabriela Der Agopian Guardia
• Support Opportunities: Scholarships in Brazil - Post-Doctoral