Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells

EMBO Mol Med. 2020 Apr 7;12(4):e11101. doi: 10.15252/emmm.201911101. Epub 2020 Mar 4.


The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome-mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.

Keywords: MYC; NOTCH; USP28; squamous cell carcinoma; ∆Np63.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell* / metabolism
  • Epithelial Cells
  • Humans
  • Mice
  • Protein Stability
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase / metabolism*


  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Trp63 protein, mouse
  • Tumor Suppressor Proteins
  • USP28 protein, human
  • USP28 protein, mouse
  • Ubiquitin Thiolesterase

Associated data

  • GEO/GSE129982