SKP2 Activation by Thyroid Hormone Receptor β2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-12, Vol.77 (24), p.6838-6850
• Main Authors: Xu, Xiaoliang L, Li, Zhengke, Liu, Aihong, Fan, Xianqun, Hu, Dan-Ning, Qi, Dong-Lai, Chitty, David W, Jia, Renbing, Qui, Jianping, Wang, Justin Q, Sharaf, Jake, Zou, Jun, Weiss, Rebecca, Huang, Hongyan, Joseph, Walter J, Ng, Lily, Rosen, Richard, Shen, Binghui, Reid, Mark W, Forrest, Douglas, Abramson, David H, Singer, Samuel, Cobrinik, David, Jhanwar, Suresh C
• Format: Article
• Language: English
• Subjects: Animals; Brain tumors; Cancer; Cell proliferation; Cell Proliferation - genetics; Cell survival; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Germ-Line Mutation; HCT116 Cells; HEK293 Cells; Humans; Mice; Mice, Knockout; Mutation; Neuroblastoma; Neuroblasts; Pituitary; Retinoblastoma; Retinoblastoma Protein - genetics; Retinoblastoma Protein - physiology; S-Phase Kinase-Associated Proteins - genetics; S-Phase Kinase-Associated Proteins - metabolism; Skp2 protein; Thyroid; Thyroid gland; Thyroid Hormone Receptors beta - physiology; Transcriptional Activation - genetics; Tumor Cells, Cultured; Tumorigenesis; Tumors; Ubiquitin; Ubiquitin-protein ligase
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-3299

Germline mutations strongly predispose humans to cone precursor-derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type-specific circuitry that sensitizes these different cell types to the loss of has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRβ2 sensitizes to loss in both settings by antagonizing the widely expressed and tumor-suppressive TRβ1. TRβ2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for -mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation. In wild-type neuroblastoma cells, endogenous Rb or ectopic TRβ2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRβ1-dependent suppression of SKP2 as a safeguard against -deficient tumorigenesis. TRβ2 counteracts TRβ1, thus disrupting this safeguard and promoting development of -deficient malignancies. .