Elevated choline drives KLF5-dominated transcriptional reprogramming to facilitate liver cancer progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090948 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28423743_1.fastq.gz | Fastqsanger.gz | |||
| SRR28423743_2.fastq.gz | Fastqsanger.gz | |||
| SRR28423744_1.fastq.gz | Fastqsanger.gz | |||
| SRR28423744_2.fastq.gz | Fastqsanger.gz | |||
| SRR28423745_1.fastq.gz | Fastqsanger.gz |
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Project description:Krüppel-like factors (Klfs) are DNA-binding transcriptional factors that regulate multiple physiological features, including the cell cycle, cell differentiation and tissue organization. Klf2, Klf4 and Klf5 are crucial for maintenance of pluripotent and somatic stem cells. We show that Klf2, Klf4 and Klf5 genes are required for normal neural development in a redundant manner and depletion of all three genes in neural precursor cells results in impaired activation of Notch signaling and early lethality. Klf5 plays a dominant role in maintenance of neural precursor cell populations by suppressing their differentiation and radial migration in developing mammalian brain. Klf4 and Klf5 also regulate proliferation of neural precursor cells in an opposing fashion. Klf4 promotes generation of quiescent neural stem cells, whereas Klf5 supports vigorously dividing intermediate progenitor cells. Our findings provide insight into mechanisms by which neural precursor cells provide large numbers of differentiating cells and a few quiescent neural stem cells.
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Project description:KLF5 is a basic transcription factor that regulates multiple biological processes, but its function in tumorigenesis appears contradictory in the current literature, with some studies showing tumor suppressor activity and others showing tumor promoting activity. In this study, we examined the function of Klf5 in prostatic tumorigenesis using mice with prostate specific deletion of Klf5 and Pten, both of which are frequently deleted in human prostate cancer. Histological and molecular analyses demonstrated that when one Pten allele was deleted, which causes mouse intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth and caused more severe morphological and molecular alterations, and homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Klf5 deletion clearly promoted tumorigenesis in luminal cells, it actually diminished the numbers of Ck5-positive basal cells in the Pten-null tumors. Klf5 deletion also increased the cell proliferation rate in tumors with Pten deletion, which involved extensive activation of the PI3K/AKT and MAPK mitogenic signaling pathways and inactivation of the p15 cell cycle inhibitor. Global gene expression and pathway analyses demonstrated that multiple mechanisms could be responsible for the tumor promoting effect of Klf5 deletion, We used microarrays to detail the global programme of gene expression of Klf5-wildtype and Klf5-null mouse dorsal prostates under Pten-null context to figure out the differential expression profiling underlying tumorigenesis
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