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  1. Home
  3. Rest-dependent Downregulation Of Von Hippel-lindau Tumor Suppressor Promotes Autophagy In Shh-medulloblastoma.
  1. Home
  3. Rest-dependent Downregulation Of Von Hippel-lindau Tumor Suppressor Promotes Autophagy In Shh-medulloblastoma.

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REST-dependent downregulation of von Hippel-Lindau tumor suppressor promotes autophagy in SHH-medulloblastoma.

Ashutosh Singh1, Donghang Cheng1, Jyothishmathi Swaminathan1

  • 1Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 853, Houston, TX, 77030, USA.

Scientific Reports
|June 12, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

The RE1 silencing transcription factor (REST) drives medulloblastoma by promoting autophagy. REST influences hypoxia-inducible factor 1-alpha (HIF1α) stability via the von Hippel-Lindau (VHL) protein, increasing tumor growth.

Keywords:
AutophagyHypoxia-inducible factor 1-alpha (HIF1α)MedulloblastomaRESTUbiquitinationVon Hippel-Lindau (VHL)

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • The RE1 silencing transcription factor (REST) is implicated in sonic hedgehog (SHH) medulloblastoma.
  • REST promotes tumor progression by enhancing proliferation, metastasis, and vascular growth while inhibiting neuronal differentiation.
  • Autophagy is a cellular process upregulated in medulloblastoma.

Purpose of the Study:

  • To investigate the role of REST in regulating autophagy in SHH medulloblastoma.
  • To elucidate the molecular mechanisms by which REST influences autophagy.
  • To explore the connection between REST, hypoxia-inducible factor 1-alpha (HIF1α), and the von Hippel-Lindau (VHL) tumor suppressor protein in medulloblastoma.

Main Methods:

  • Analysis of REST expression and its correlation with autophagy markers in SHH medulloblastoma xenografts and human tumors.
  • Investigation of HIF1α localization and VHL protein levels in response to REST modulation in vitro.
  • Assessment of HIF1α ubiquitination and autophagy flux under varying REST and VHL conditions.

    • Main Results:

    • REST elevation in SHH medulloblastoma is correlated with increased autophagy, HIF1α expression, and decreased VHL expression.
    • REST knockdown leads to increased VHL, reduced cytoplasmic HIF1α, and decreased autophagy flux.
    • REST overexpression reduces VHL levels and its interaction with HIF1α, decreasing HIF1α ubiquitination and increasing autophagy flux.

    Conclusions:

    • REST promotes autophagy in SHH medulloblastoma by modulating HIF1α ubiquitination and stability in a VHL-dependent manner.
    • This study establishes a link between VHL, REST, and autophagy regulation in a subset of medulloblastomas.
    • REST-driven autophagy may represent a therapeutic target in SHH medulloblastoma.