SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development.

in The EMBO journal by Madalina Raducu, Ella Fung, Sébastien Serres, Paola Infante, Alessandro Barberis, Roman Fischer, Claire Bristow, Marie-Laëtitia Thézénas, Csaba Finta, John C Christianson, Francesca M Buffa, Benedikt M Kessler, Nicola R Sibson, Lucia Di Marcotullio, Rune Toftgård, Vincenzo D'Angiolella

TLDR

  • The study investigates how a protein called Fbxl17 controls another protein called Sufu, which is important for a signaling pathway called Hh. The study shows that Fbxl17 targets Sufu for proteolysis in the nucleus, which leads to defective Hh signaling and impaired cancer cell proliferation. The study also identifies a mutation in Sufu that increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to sustained Hh signaling activation in medulloblastoma. In summary, the study reveals that Fbxl17 plays a crucial role in the Hh pathway and its impact on tumor growth in medulloblastoma.

Abstract

Skp1-Cul1-F-box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma-associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17-Sufu axis in the pathogenesis of medulloblastoma.

Overview

  • The study investigates the role of Fbxl17 in controlling Sufu levels and its impact on Hh signaling and tumor growth in medulloblastoma. The study uses a combination of in vitro and in vivo experiments to test the hypothesis that Fbxl17 targets Sufu for proteolysis in the nucleus, leading to defective Hh signaling and impaired cancer cell proliferation. The study also identifies a mutation in Sufu that increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to sustained Hh signaling activation in medulloblastoma patients with Gorlin syndrome. The methodology used for the experiment includes cell culture, immunoprecipitation, Western blotting, and mouse models of medulloblastoma. The primary objective of the study is to identify the role of Fbxl17 in the Hh pathway and its impact on tumor growth in medulloblastoma.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the effects of Fbxl17 depletion on Hh signaling and cancer cell proliferation. The results show that depletion of Fbxl17 leads to defective Hh signaling and impaired cancer cell proliferation. The study also identifies a mutation in Sufu that increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to sustained Hh signaling activation in medulloblastoma patients with Gorlin syndrome. The key findings of the study are that Fbxl17 targets Sufu for proteolysis in the nucleus, leading to defective Hh signaling and impaired cancer cell proliferation, and that a mutation in Sufu increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to sustained Hh signaling activation in medulloblastoma. These findings support the hypothesis that Fbxl17 plays a crucial role in the Hh pathway and its impact on tumor growth in medulloblastoma.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they identify Fbxl17 as a novel regulator of the Hh pathway and highlight the perturbation of the Fbxl17-Sufu axis in the pathogenesis of medulloblastoma. The study also identifies a mutation in Sufu that increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to sustained Hh signaling activation in medulloblastoma patients with Gorlin syndrome. Future research directions could include further investigation of the role of Fbxl17 in the Hh pathway and its impact on other cancers, as well as the development of targeted therapies to modulate Fbxl17 activity in cancer cells. The study also highlights the importance of understanding the molecular mechanisms underlying the Hh pathway and its impact on tumor growth, which could lead to the development of more effective treatments for medulloblastoma and other cancers.
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