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

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.

Automated summary

Hedgehog signaling mediated by Ci/Gli plays a key role in development and homeostasis, and dysregulation can lead to human disorders. Cofactors of Ci/Gli that affect tumorigenesis are not well understood. Through genetic screening in Drosophila, the researchers found that overexpression of active Ci alone is not sufficient to generate a tumor-like phenotype, but when combined with knockdown of hib, it leads to a striking tumor-like big eye phenotype. Mechanistically, HIB/SPOP inhibits tumorigenesis by modulating the stability of RNA polymerase II (RNAPII) components. Additionally, Ci/Gli can promote HIB/SPOP-mediated degradation of Rpb7/Rpb3. The results indicate the importance of Ci/Gli and suitable RNAPII interaction in achieving the tumor-like eye phenotype and highlight the dual role of HIB/SPOP in controlling tumorigenesis.