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<p><i>The USP37</i> gene encodes a deubiquitylase (DUB), which catalyzes the proteolytic removal of ubiquitin moieties from proteins to modulate their stability, cellular localization or activity. Its expression is downregulated in a subgroup of medulloblastomas driven by constitutive activation of sonic hedgehog (SHH) signaling. Patients with SHH-driven medulloblastomas with elevated expression of the <i>RE1</i> silencing transcription factor (REST) and reduced expression of <i>USP37</i> have poor outcomes. In previous studies, we showed sustained proliferation of SHH-medulloblastoma cells due to blockade of terminal cell cycle exit and neuronal differentiation stemming from a failure in USP37-dependent stabilization of its target, the cyclin-dependent kinase inhibitor (CDKI)-p27. This finding suggested a tumor suppressive function for USP37. Interestingly, the current study also uncovered Raptor, a component of the mTORC1 complex, as a novel target of USP37. Under conditions of low-<i>USP37</i> expression, reduced Raptor stability and mTORC1 activity caused a decline in phosphorylation of 4E-binding protein 1 (4EBP1) and increased its interaction with eukaryotic elongation factor 4E (eIF4E), which is known to inhibit CAP-dependent translation initiation. Surprisingly, a subset of patients with SHH-driven medulloblastomas with elevated expression of <i>USP37</i> and the Glioma-associated Oncogene 1 (<i>GLI1</i>), also exhibited poor outcomes. Using genetic and biochemical analyses, we showed that USP37-mediated stabilization of GLI1, a terminal effector of SHH signaling, increases pathway activity and upregulates expression of its target oncogene product, CCND1, to drive cell proliferation. These data indicate that USP37 elevation in SHH-driven medulloblastomas has the potential to promote non-canonical activation of SHH signaling. Overall, our findings suggest that USP37 may have context-specific oncogenic and tumor suppressive roles in medulloblastoma cells.</p>

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Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Ashutosh Singh,
  • Donghang Cheng,
  • Amanda R. Haltom,
  • Yanwen Yang,
  • Tara Dobson,
  • Rashieda Hatcher,
  • Veena Rajaram,
  • Vidya Gopalakrishnan

摘要

The USP37 gene encodes a deubiquitylase (DUB), which catalyzes the proteolytic removal of ubiquitin moieties from proteins to modulate their stability, cellular localization or activity. Its expression is downregulated in a subgroup of medulloblastomas driven by constitutive activation of sonic hedgehog (SHH) signaling. Patients with SHH-driven medulloblastomas with elevated expression of the RE1 silencing transcription factor (REST) and reduced expression of USP37 have poor outcomes. In previous studies, we showed sustained proliferation of SHH-medulloblastoma cells due to blockade of terminal cell cycle exit and neuronal differentiation stemming from a failure in USP37-dependent stabilization of its target, the cyclin-dependent kinase inhibitor (CDKI)-p27. This finding suggested a tumor suppressive function for USP37. Interestingly, the current study also uncovered Raptor, a component of the mTORC1 complex, as a novel target of USP37. Under conditions of low-USP37 expression, reduced Raptor stability and mTORC1 activity caused a decline in phosphorylation of 4E-binding protein 1 (4EBP1) and increased its interaction with eukaryotic elongation factor 4E (eIF4E), which is known to inhibit CAP-dependent translation initiation. Surprisingly, a subset of patients with SHH-driven medulloblastomas with elevated expression of USP37 and the Glioma-associated Oncogene 1 (GLI1), also exhibited poor outcomes. Using genetic and biochemical analyses, we showed that USP37-mediated stabilization of GLI1, a terminal effector of SHH signaling, increases pathway activity and upregulates expression of its target oncogene product, CCND1, to drive cell proliferation. These data indicate that USP37 elevation in SHH-driven medulloblastomas has the potential to promote non-canonical activation of SHH signaling. Overall, our findings suggest that USP37 may have context-specific oncogenic and tumor suppressive roles in medulloblastoma cells.