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Ubiquitin-specific protease 11 (USP11) functions as a tumor suppressor through deubiquitinating and stabilizing VGLL4

Encheng Zhang1, Bing Shen1, Xingyu Mu1

  • 1Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University Shanghai, P. R. China.

American Journal of Cancer Research
|January 3, 2017
PubMed

Insights

The deubiquitinating enzyme USP11 stabilizes VGLL4 protein, a key repressor of cancer growth. USP11

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • VGLL4 (Vestigial-like protein 4) is a transcriptional repressor that inhibits YAP-induced overgrowth and tumorigenesis.
  • VGLL4 protein levels are significantly reduced in various human cancers, but its post-transcriptional regulation remains unclear.
  • The YAP/TEADs pathway is a critical regulator of cell proliferation and is often dysregulated in cancer.

Purpose of the Study:

  • To investigate the post-transcriptional regulation of VGLL4 protein.
  • To identify novel interactors and regulators of VGLL4.
  • To elucidate the role of USP11 in the VGLL4/YAP-TEADs regulatory loop and its implications in cancer.

Main Methods:

  • Co-immunoprecipitation assays to identify VGLL4 interactors.
  • Western blotting and ubiquitination assays to assess VGLL4 protein stability.
  • Cell proliferation, migration, and invasion assays after USP11 knockdown.
  • Analysis of the interaction domains between USP11 and VGLL4.

Main Results:

  • Deubiquitinating enzyme USP11 was identified as a novel interactor of VGLL4.
  • The USP domain of USP11 and the N-terminal region of VGLL4 are essential for their binding.
  • USP11 promotes VGLL4 protein stability by deubiquitination, thereby inhibiting YAP-dependent cell growth, migration, and invasion.
  • Knockdown of USP11 leads to increased cell proliferation, migration, and invasion in a YAP-dependent manner.

Conclusions:

  • USP11 deubiquitinates and stabilizes VGLL4 protein.
  • USP11 acts as a tumor suppressor by modulating the VGLL4/YAP-TEADs regulatory loop.
  • USP11 represents a potential therapeutic target for cancers with dysregulated YAP signaling.
Keywords:
Hippo pathwayTEADsUSP11VGLL4deubiquitination

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