Transglutaminase 2 promotes tumorigenicity of colon cancer cells by inactivation of the tumor suppressor p53.
Animals
Apoptosis
/ genetics
Carcinogenesis
/ genetics
Caspase 3
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Colon
/ pathology
Colonic Neoplasms
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
HCT116 Cells
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Protein Glutamine gamma Glutamyltransferase 2
/ genetics
Protein Interaction Maps
/ genetics
Transcriptome
/ genetics
Tumor Suppressor Protein p53
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
04
11
2020
accepted:
17
05
2021
revised:
30
04
2021
pubmed:
10
6
2021
medline:
22
12
2021
entrez:
9
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34103685
doi: 10.1038/s41388-021-01847-w
pii: 10.1038/s41388-021-01847-w
pmc: PMC8225513
doi:
Substances chimiques
TGM2 protein, human
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Protein Glutamine gamma Glutamyltransferase 2
EC 2.3.2.13
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4352-4367Références
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