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

被引：44

作者：

Prieto-Garcia, Cristian ^{[1
,2
]}

Hartmann, Oliver ^{[1
,2
]}

Reissland, Michaela ^{[1
,2
]}

Braun, Fabian ^{[1
,2
]}

Fischer, Thomas ^{[1
,3
]}

Walz, Susanne ^{[4
]}

Schuelein-Voelk, Christina ^{[5
]}

Eilers, Ursula ^{[5
]}

Ade, Carsten P. ^{[2
,6
]}

Calzado, Marco A. ^{[7
,8
,9
]}

Orian, Amir ^{[10
]}

Maric, Hans M. ^{[11
]}

Muench, Christian ^{[12
]}

Rosenfeldt, Mathias ^{[2
,13
]}

Eilers, Martin ^{[2
,6
]}

Diefenbacher, Markus E. ^{[1
,2
]}

机构：

[1] Univ Wurzburg, Dept Biochem & Mol Biol, Prot Stabil & Canc Grp, Wurzburg, Germany

[2] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany

[3] Univ Hosp Wurzburg, Dept Radiotherapy, Wurzburg, Germany

[4] Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Core Unit Bioinformat, Wurzburg, Germany

[5] Univ Wurzburg, Bioctr, Core Unit High Content Microscopy, Wurzburg, Germany

[6] Univ Wurzburg, Dept Biochem & Mol Biol, Wurzburg, Germany

[7] Inst Maimonides Invest Biomed Cordoba IMIBIC, Cordoba, Spain

[8] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Cordoba, Spain

[9] Hosp Univ Reina Sofia, Cordoba, Spain

[10] Technion Haifa, Fac Med, TICC, Haifa, Israel

[11] Rudolf Virchow Ctr Expt Biomed, Wurzburg, Germany

[12] Goethe Univ, Inst Biochem 2, Frankfurt, Germany

[13] Univ Wurzburg, Inst Pathol, Wurzburg, Germany

来源：

EMBO MOLECULAR MEDICINE | 2020年 / 12卷 / 04期

关键词：

increment Np63; MYC; NOTCH; squamous cell carcinoma; USP28; INTESTINAL HOMEOSTASIS; CENTROSOME LOSS; P63; EXPRESSION; CARCINOMA; GENE; FBW7; PROLIFERATION; UBIQUITINATION; TUMORIGENESIS;

D O I：

10.15252/emmm.201911101

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The transcription factor increment 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 increment Np63 and maintains elevated increment 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 increment Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.

引用

页数：25

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