Transglutaminase 2 promotes tumorigenicity of colon cancer cells by inactivation of the tumor suppressor p53

  • Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target. In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein–protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction. We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.
Metadaten
Author:Patrizia MalkomesGND, Ilaria LungerORCiDGND, Elsie Oppermann, Khalil Abou-El-ArdatORCiDGND, Thomas OellerichORCiD, Stefan GüntherORCiD, Can Canbulat, Sabrina Bothur, Frank SchnütgenORCiDGND, Weijia YuORCiDGND, Susanne WingertGND, Nadine HätscherGND, Claudia Catapano, Marina DietzORCiDGND, Mike HeilemannORCiDGND, Hans Michael KvasnickaORCiD, Katharina Holzer, Hubert ServeORCiDGND, Wolf Otto BechsteinORCiDGND, Michael A. RiegerORCiDGND
URN:urn:nbn:de:hebis:30:3-636142
DOI:https://doi.org/10.1038/s41388-021-01847-w
ISSN:1476-5594
Parent Title (English):Oncogene
Publisher:Springer Nature
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2021/06/08
Date of first Publication:2021/06/08
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/07/12
Tag:Colorectal cancer; Oncogenes
Volume:40.2021
Issue:25
Page Number:16
First Page:4352
Last Page:4367
Note:
The study was supported in part by the Else Kröner Fresenius-Stiftung, the Deutsche Krebshilfe (both to P.M.) and by the LOEWE Centers Cell and Gene Therapy Frankfurt (Hessen State Ministry for Higher Education, Research and the Arts, III L 4- 518/17.004 [2014]) and Frankfurt Cancer Institute (Hessen State Ministry for Higher Education, Research and the Arts, III L 5 − 519/03/03.001 – [0015]). Open Access funding enabled and organized by Projekt DEAL.
HeBIS-PPN:502149329
Institutes:Biochemie, Chemie und Pharmazie
Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0