Prieto-Garcia Cristian, Hartmann Oliver, Reissland Michaela, Braun Fabian, Fischer Thomas, Walz Susanne, Schülein-Völk Christina, Eilers Ursula, Ade Carsten P, Calzado Marco A, Orian Amir, Maric Hans M, Münch Christian, Rosenfeldt Mathias, Eilers Martin, Diefenbacher Markus E
Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.
Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.
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.
转录因子ΔNp63是上皮细胞特性的主要调节因子，对肺、头颈部、食管、子宫颈和皮肤的鳞状细胞癌（SCC）的存活至关重要。在此，我们报告去泛素化酶USP28通过抵消蛋白酶体介导的降解来稳定ΔNp63，并在SCC中维持升高的ΔNP63水平。无论是通过基因手段还是药理学手段损害USP28活性，都会消除转录特性并抑制人SCC细胞的生长和存活。CRISPR/Cas9工程化的体内小鼠模型证实，内源性USP28对于肺SCC的诱导和维持都是绝对必需的。我们的数据强烈表明，通过抑制USP28来靶向ΔNp63丰度是治疗SCC肿瘤的一种有前景的策略。
