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

Abstract

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.

A novel application of hectorite nanoclay for preparation of colorectal cancer spheroids with malignant potential

“…The expression of these genes is increased in human colon cancer tissues in comparison to normal tissues, and is associated with tumorigenesis. 37,38 The increased expression of these genes was further confirmed by RT-qPCR analysis. As shown in Fig.…”

Comprehensive machine-learning survival framework develops a consensus model in large-scale multicenter cohorts for pancreatic cancer

“…After careful literature research, we found that SELENBP1 that owned lower expression in the low AIDPS group with poor prognosis was associated with better tumor prognosis, and its decreased expression led to poor prognosis of many tumors such as lung adenocarcinoma ( Chen et al, 2004 ). Meanwhile, PRR11 , EREG , ADM, and TGM2 , which were overexpressed in the low AIDPS group, played a vital role in the proliferation, invasion, and metastasis of many tumors such as breast cancer, colorectal cancer, and PACA, and lead to their chemotherapy resistance and were potential targets for enhanced efficacy ( Lee et al, 2020 ; Neufert et al, 2013 ; Aggarwal et al, 2012 ; Malkomes et al, 2021 ). In addition, our study also found strong biological correlations among nine AIDPS genes, which are also closely related to mutations, CNAs, and TME in PACA.…”

“… In addition, currently one of the few studies supports the oncogenic role of cell division cycle-associated protein 4 (CDCA4) in tumors and nuclear factors induced as E2F transcription factor families that regulate E2F-dependent transcriptional activation and cell proliferation, but their potential mechanism, especially effects on PACA tumorigenesis and progression, requires further investigation ( Fang et al, 2022 ; Hayashi et al, 2006 ). Transglutaminase 2 (TGM2), a promoter of stemness and radiotherapy resistance in glioma ( Berg et al, 2021 ), has been confirmed in many studies to promote colorectal cancer progression via P53 and Wnt/β-catenin signaling pathways ( Malkomes et al, 2021 ; Gu et al, 2019 ), as well as is associated with tumor-promoting inflammation in gastric cancer ( Cho et al, 2020 ). These results are consistent with the TGM2 expression dramatically increased in the low AIDPS group with worse prognosis, suggesting that TGM2 may play an important role in the development and progression of PACA.…”

“…Transglutaminase 2 (TGM2), a promoter of stemness and radiotherapy resistance in glioma ( Berg et al, 2021 ), has been confirmed in many studies to promote colorectal cancer progression via P53 and Wnt/β-catenin signaling pathways ( Malkomes et al, 2021 ; Gu et al, 2019 ), as well as is associated with tumor-promoting inflammation in gastric cancer ( Cho et al, 2020 ). These results are consistent with the TGM2 expression dramatically increased in the low AIDPS group with worse prognosis, suggesting that TGM2 may play an important role in the development and progression of PACA.…”

Type 2 transglutaminase in the nucleus: the new epigenetic face of a cytoplasmic enzyme

“…There is a general consensus that TG2 expression is upregulated in various tumors and this is associated with p53 instability [ 23 , 27 , 42 , 79 ]. In renal cell carcinoma it has been shown that the downregulation of TG2 stabilizes p53 expression, thereby inducing an increase in apoptosis.…”