TY  - JOUR
A1  - Malkomes, Patrizia
A1  - Lunger, Ilaria
A1  - Oppermann, Elsie
A1  - Abou-El-Ardat, Khalil
A1  - Oellerich, Thomas
A1  - Günther, Stefan
A1  - Canbulat, Can
A1  - Bothur, Sabrina
A1  - Schnütgen, Frank
A1  - Yu, Weijia
A1  - Wingert, Susanne
A1  - Hätscher, Nadine
A1  - Catapano, Claudia
A1  - Dietz, Marina
A1  - Heilemann, Mike
A1  - Kvasnicka, Hans Michael
A1  - Holzer, Katharina
A1  - Serve, Hubert
A1  - Bechstein, Wolf Otto
A1  - Rieger, Michael A.
T1  - Transglutaminase 2 promotes tumorigenicity of colon cancer cells by inactivation of the tumor suppressor p53
T2  - Oncogene
N2  - 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.
KW  - Colorectal cancer
KW  - Oncogenes
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63614
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-636142
SN  - 1476-5594
N1  - 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.
VL  - 40.2021
IS  - 25
SP  - 4352
EP  - 4367
PB  - Springer Nature
CY  - London
ER  -