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The deubiquitinase USP7 promotes HNSCC progression via deubiquitinating and stabilizing TAZ

Jin Li1,2,3, Yibin Dai1,2,3, Han Ge1

  • 1Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu, People's Republic of China.

Cell Death & Disease
|August 5, 2022
PubMed

Insights

Researchers discovered USP7 stabilizes the TAZ protein, promoting head and neck squamous cell carcinoma (HNSCC) growth. Inhibiting USP7 suppressed tumor growth, identifying the USP7-TAZ axis as a potential therapeutic target for HNSCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Dysregulation of the Hippo signaling pathway effector TAZ is implicated in various cancers, including head and neck squamous cell carcinoma (HNSCC).
  • TAZ protein stability is regulated by ubiquitination and degradation, primarily mediated by the E3 ligase β-TRCP, but the role of deubiquitinating enzymes is not well understood.

Purpose of the Study:

  • To identify deubiquitinating enzymes that regulate TAZ protein stability in HNSCC.
  • To elucidate the mechanism by which USP7 affects TAZ and its role in HNSCC progression.
  • To evaluate USP7 as a potential therapeutic target for HNSCC.

Main Methods:

  • Utilized siRNA and cDNA library screening to identify deubiquitinating enzymes.
  • Investigated USP7-TAZ interaction and deubiquitination activity.
  • Assessed the impact of USP7 on TAZ protein levels, nuclear localization, and transcriptional activity.
  • Evaluated USP7 overexpression in HNSCC patient samples.
  • Tested the efficacy of USP7 inhibition in preclinical HNSCC models (xenograft and PDX).

Main Results:

  • USP7 was identified as a key deubiquitinase for TAZ in HNSCC.
  • USP7 stabilizes TAZ by removing K48-linked ubiquitination, independent of the canonical Hippo pathway.
  • USP7 promotes HNSCC cell proliferation, migration, invasion, and tumor growth by enhancing TAZ stability and transcriptional output.
  • USP7 overexpression correlates with TAZ upregulation, tumor aggressiveness, and poor prognosis in HNSCC patients.
  • Pharmacological inhibition of USP7 effectively suppressed tumor growth in vivo.

Conclusions:

  • USP7 is a critical regulator of TAZ stability and function in HNSCC.
  • The USP7-TAZ signaling axis represents a novel and promising therapeutic target for HNSCC.
  • USP7 may serve as a valuable biomarker for predicting HNSCC aggressiveness and patient prognosis.

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