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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
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SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes
Ken Tajima1, Toshifumi Yae1, Sarah Javaid1
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nature Communications
|September 24, 2015
Summary
The histone methyltransferase SETD1A suppresses the cancer gene BTG2 indirectly via microRNAs, impacting cell cycle and tumor growth. This reveals a novel mechanism for gene silencing in cancer.
Area of Science:
- Cancer Biology
- Epigenetics
- Gene Regulation
Background:
- The antiproliferative gene BTG2 is often downregulated in cancers without direct mutations.
- Alternative gene silencing mechanisms for BTG2 are suggested.
- Histone lysine methyltransferases (KMTs) are implicated in cancer development.
Purpose of the Study:
- To identify the mechanism suppressing BTG2 expression in cancer.
- To investigate the role of KMTs in regulating BTG2.
- To understand how chromatin regulators impact cancer-related genes.
Main Methods:
- shRNA screen targeting 43 histone lysine methyltransferases (KMTs).
- Analysis of miRNA induction and gene expression.
- In vitro cell cycle assays.
- Mouse xenograft models for tumorigenesis studies.
Main Results:
- SETD1A was identified as a suppressor of BTG2 expression.
- SETD1A induces BTG2-targeting microRNAs (miRNAs), leading to gene downregulation.
- This indirect miRNA-dependent mechanism affects multiple p53 pathway genes.
- SETD1A regulates cell cycle progression and modulates tumorigenesis in vivo.
Conclusions:
- SETD1A suppresses BTG2 via an indirect miRNA-dependent mechanism.
- This pathway explains specific genetic consequences of chromatin modulator alterations in cancer.
- Findings elucidate a novel epigenetic regulation of tumor suppressor genes.
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