Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability

  • Dev Cell. 2020 Dec 21;55(6):707-722.e9. doi: 10.1016/j.devcel.2020.11.012.
Guobin Xie  1 ,  Yuqi Zhou  2 ,  Xuhuang Tu  1 ,  Xiaohong Ye  1 ,  Lin Xu  1 ,  Zhijian Xiao  1 ,  Qiqiang Wang  1 ,  Xin Wang  1 ,  Mingxuan Du  1 ,  Ziwen Chen  2 ,  Xiaoqin Chi  3 ,  Xiaoli Zhang  1 ,  Ji Xia  1 ,  Xiaowei Zhang  1 ,  Yunxia Zhou  1 ,  Zongxi Li  1 ,  Chengrong Xie  3 ,  Luoyan Sheng  1 ,  Zhiping Zeng  1 ,  Hu Zhou  1 ,  Zhenyu Yin  3 ,  Ying Su  2 ,  Yang Xu  1 ,  Xiao-Kun Zhang  4
Affiliations
  • 1. School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China.
  • 2. School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China; NucMito Pharmaceuticals Co. Ltd., Xiamen 361101, Fujian, China.
  • 3. Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen 361004, Fujian, China.
  • 4. School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, Fujian, China. Electronic address: [email protected].
PMID: 33321102 DOI: 10.1016/j.devcel.2020.11.012
Abstract

Retinoid X receptor Alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and Apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (CDK1) at the onset of Mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in Cancer cell lines, during carcinogenesis in Animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during Mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index.

Keywords
Cdk1; PLK1; RXRα; RXRα ligand; RXRα phosphorylation; catastrophe; centrosome; mitosis; nuclear receptor; tumor vulnerability.
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