PRDM1 silences stem cell-related genes and inhibits proliferation of human colon tumor organoids
Menée in vitro à l'aide d'organoïdes de tumeurs du côlon, cette étude met en évidence des mécanismes par lesquels, en lien avec p53, la protéine PRDM1 exerce une fonction de suppresseur de tumeurs
Our previous studies demonstrated that PRDM1β is activated by p53 accumulation 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. Also, PRDM1α and PRDM1β proteins repress a largely overlapping suite of genes, many of which are stem cell-related genes. Moreover, we show that forced expression of PRDM1β prevents the proliferation of colon tumor organoids. This work provides support for a role of PRDM1β in regulating normal colon stem cell proliferation. 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.