PRDM1 silences stem cell-related genes and inhibits proliferation of human colon tumor organoids

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 22; pp. E5066 - E5075
• Main Authors: Liu, Changlong, Banister, Carolyn E., Weige, Charles C., Altomare, Diego, Richardson, Joseph H., Contreras, Carlo M., Buckhaults, Phillip J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29-05-2018
• Series: PNAS Plus
• Subjects: Biological Sciences; Cancer; Cell Line, Tumor; Cell Proliferation - physiology; Cell size; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Colon - chemistry; Colon - metabolism; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - mortality; Colorectal cancer; Colorectal carcinoma; Deoxyribonucleic acid; Disease-Free Survival; DNA; DNA damage; Gene expression; Gene silencing; Genes; Human behavior; Humans; Intestine; Isoforms; Lymphocytes; Lymphocytes B; Lymphocytes T; Myc protein; Organoids; Organoids - cytology; Organoids - metabolism; p53 Protein; PNAS Plus; Positive Regulatory Domain I-Binding Factor 1 - genetics; Positive Regulatory Domain I-Binding Factor 1 - metabolism; Positive Regulatory Domain I-Binding Factor 1 - physiology; Stem cells; Studies; Transcription; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; CRISPR; colorectal cancer; PRDM1; TP53; organoids
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1802902115

PRDM1 is a tumor suppressor that plays an important role in B and T cell lymphomas. Our previous studies demonstrated that PRDM1β is a p53-response gene in human colorectal cancer cells. However, the function of PRDM1β in colorectal cancer cells and colon tumor organoids is not clear. Here we show that PRDM1β is a p53-response gene in human colon organoids and that low PRDM1 expression predicts poor survival in colon cancer patients. We engineered PRDM1 knockouts and overexpression clones in RKO cells and characterized the PRDM1-dependent transcript landscapes, revealing that both the α and β transcript isoforms repress MYC-response genes and stem cell-related genes. Finally, we show that forced expression of PRDM1 in human colon cancer organoids prevents the formation and growth of colon tumor organoids in vitro. These results suggest that p53 may exert tumor-suppressive effects in part through a PRDM1-dependent silencing of stem cell genes, depleting the size of the normal intestinal stem cell compartment in response to DNA damage.