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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.
Purpose: Colorectal cancer (CRC) is the second most common cancer in Germany. Around 60,000 people were diagnosed CRC in 2016 in Germany. Since 2019, screening colonoscopies are offered in Germany for men by the age of 50 and for women by the age of 55. It is recently discussed if women should also undergo a screening colonoscopy by the age of 50 and if there are any predictors for getting CRC.
Methods: Colonoscopies of 1553 symptomatic patients younger than 55 years were compared with colonoscopies of 1075 symptomatic patients older than 55 years. We analyzed if there are any significant differences between those two groups in the prevalence of CRC and its precursor lesions or between symptomatic men and women. We evaluated if there is a correlation between abdominal symptoms and the prevalence of CRC.
Results: In 164/1553 symptomatic patients, 194 (12.5%) polyps were detected. In total, six colorectal carcinomas (0.4%) were detected. There were no significant differences between men and women. In symptomatic patients ≥ 55 years, significantly more polyps were found (p<0.0001; 26.6% vs. 12.5%). Totally, 286 polyps (26.6%) were removed in 1075 symptomatic patients older than 55 years. Anorectal bleeding was the only abdominal symptom being a significant indicator for the prevalence of the occurrence of colon and rectum cancer in both groups (p=0.03, OR=2.73 95%-CI [1.11;6.70]), but with only low sensitivity (44%).
Conclusion: Due to no significant differences in men and women, we recommend screening colonoscopies also for women by the age of 50.