SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26394836.
- Also identified by DOI 10.1038/ncomms9257 and PMC identifier 4667427.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer.
Medical subject headings
- Cell Cycle
- Gene Expression Regulation, Neoplastic
- Histone-Lysine N-Methyltransferase
- Immediate-Early Proteins
- MicroRNAs
- Tumor Suppressor Proteins