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

ABSTRACT: PRDM1 is a tumor suppressor that plays an important role in B and T cell lymphomas. Our previous studies demonstrated that PRDM1? is a p53-response gene in human colorectal cancer cells. However, the function of PRDM1? in colorectal cancer cells and colon tumor organoids is not clear. Here we show that PRDM1? 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 ? and ? 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.

SUBMITTER: Liu C

PROVIDER: S-EPMC5984534 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Liu Changlong C Banister Carolyn E CE Weige Charles C CC Altomare Diego D Richardson Joseph H JH Contreras Carlo M CM Buckhaults Phillip J PJ

Proceedings of the National Academy of Sciences of the United States of America 20180514 22

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 ...[more]

PMID: 29760071

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Project description:BackgroundAccumulative evidence shows that an organoid is a more practical and reliable tool in cancer biology research. This study aimed to identify and validate crucial genes involved in non-small cell lung cancer carcinogenesis and development using the transcriptomic analysis of tumor tissues and organoids.MethodsGene set enrichment analysis (GSEA) of tumor tissues, tumor organoids, and normal tissues was performed to reveal the similar and different mechanisms involved in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) carcinogenesis and progression. Differentially expressed gene analysis, prognostic analysis, and gene co-expression network analysis were further used to identify hub genes involved in LUAD and LUSC carcinogenesis and development. Finally, LUAD cell lines and organoids were used to validate these findings.ResultsGSEA analysis was performed to reveal the similar mechanisms involved in LUAD and LUSC carcinogenesis and development, such as P53 signaling pathway, base mismatch repair, DNA replication, cAMP signaling pathway and PPAR pathway. However, comparing with LUSC organoids, LUAD organoids showed downregulation of immune-related pathways, inflammation-related pathways, MAPK signaling pathways, and Rap1 signaling pathways, although these pathways were downregulated in LUAD and LUSC tissues by comparing with normal lung tissues. Further gene co-expression network analysis and prognostic analysis indicated CDK1, CCNB2, and CDC25A as the hub tumor-promoting genes in LUAD but not in LUSC, which were further validated in other datasets. Using LUAD cell lines and organoid models, CDK1 and CCNB2 knockdown were found to suppress LUAD proliferation. However, CDC25A knockdown did not inhibit LUAD cell line proliferation but could effectively suppress LUAD organoid growth, indicating that an organoid could be used as an effective tool to study cancer biology in LUAD.ConclusionsThe results revealed CDK1, CCNB2, and CDC25A as the hub genes involved in LUAD carcinogenesis and development, which could be used as the potential biomarkers and targets for LUAD.

Dataset Information

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

Publications

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

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