A role of HAUSP in tumor suppression in a human colon carcinoma xenograft model.
The protease HAUSP is a critical component of the p53-Mdm2 pathway and acts as a specific deubiquitinase for both p53 and Mdm2 and thus is important for p53 regulation. In knock-down and knock-out cellular systems it was observed that ablation of HAUSP induces profound stabilization of p53 due to enhanced degradation of Mdm2. Thus, inhibiting HAUSP by small compound interference has been proposed as a rational therapeutic strategy to activate p53 in p53 wild type tumors. However, HAUSP-mediated effects in the p53-Mdm2 axis are highly complex and non-linear and to date the role of HAUSP in tumor suppression in vivo remains unexplored. Here we investigate the effect of HAUSP up and downregulation on cell proliferation, apoptosis and tumor growth in vitro and in a xenograft model in vivo, using an inducible isogenic human colon carcinoma cell system. Importantly, in the absence of stress, both HAUSP up and downregulation inhibit cell proliferation in vitro and tumor growth in vivo due to constitutively elevated p53 levels. Moreover, tumors with HAUSP up and downregulation respond to radiotherapy with further growth inhibition. However, HAUSP downregulation causes resistance to Camptothecin- and irradiation-induced apoptosis, which correlates with suppressed mitochondrial translocation of p53. Our data suggest that changes in HAUSP modulate tumor growth and apoptotic sensitivity in vivo.
Becker
Kerstin
K
Department of Pathology, Stony Brook University, Stony Brook, New York, USA.
Marchenko
Natalia D
ND
Palacios
Gustavo
G
Moll
Ute M
UM
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011878:Radiotherapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination; D015854:Up-Regulation / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7