HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA Polymerase II components stabilities

Yuxue Gao; Zhaoliang Shan; Chunhua Jian; Ying Wang; Xia Yao; Shengnan Li; Xiuxiu Ti; Guochun Zhao; Chen Liu; Qing Zhang

doi:10.1016/j.isci.2023.107334

HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA Polymerase II components stabilities

iScience. 2023 Jul 10;26(8):107334. doi: 10.1016/j.isci.2023.107334. eCollection 2023 Aug 18.

Authors

Yuxue Gao¹, Zhaoliang Shan¹, Chunhua Jian¹, Ying Wang¹, Xia Yao¹, Shengnan Li¹, Xiuxiu Ti¹, Guochun Zhao¹, Chen Liu², Qing Zhang¹

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, China.
² Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China.

Abstract

Hedgehog (Hh) signaling mediated by transcription factor Ci/Gli plays a vital role in embryonic development and adult tissue homeostasis in invertebrates and vertebrates, whose dysregulation leads to many human disorders, including cancer. However, till now, cofactors of Ci/Gli which can affect tumorigenesis are not well known. Here, through genetic screen, we find overexpression of active Ci alone is not sufficient to generate tumor-like eye phenotype in Drosophila, however, its overexpression combined with knockdown of hib causes a striking tumor-like big eye phenotype. Mechanistically, HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA polymerase II (RNAPII) components Rpb3/Rpb7 stabilities in E3 ligase dependent manner. In addition, Ci/Gli can promote HIB/SPOP-mediated Rpb7/Rpb3 degradation. Taken together, our results indicate Ci/Gli needs to hook up with suitable RNAPII together to achieve the tumor-like eye phenotype and HIB/SPOP plays dual roles through controlling Ci/Gli and Rpb3/Rpb7 protein stabilities to temper Ci/Gli/RNAPII-mediated tumorigenesis.

Keywords: Cell biology; Genetics; Model organism.