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Genome-wide Screen for miRNA Targets Using the MISSION Target ID Library
Published on: April 6, 2012
Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155
Suhwan Chang1, Rui-Hong Wang, Keiko Akagi
1Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
Nature Medicine
|September 28, 2011
Summary
The BRCA1 tumor suppressor normally represses miR-155, an oncomir. A moderate-risk BRCA1 variant (R1699Q) abrogates this repression, suggesting miR-155 as a therapeutic target for BRCA1-deficient tumors.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- BRCA1 is a tumor suppressor primarily known for DNA repair and cell cycle regulation.
- Investigating low-penetrant BRCA1 variants can reveal novel physiological functions.
- MicroRNA-155 (miR-155) is an oncomir implicated in cancer development.
Purpose of the Study:
- To investigate the functional impact of the moderate-risk BRCA1 R1699Q variant.
- To explore the relationship between BRCA1 and miR-155 expression.
- To elucidate the mechanism of BRCA1-mediated repression of miR-155.
Main Methods:
- Studied the BRCA1 R1699Q variant in cell lines.
- Assessed DNA damage repair capacity.
- Investigated BRCA1's interaction with HDAC2 and its effect on miR-155 promoter.
- Performed in vivo tumor cell growth assays with miR-155 overexpression and knockdown.
Main Results:
- The BRCA1 R1699Q variant does not impair DNA damage repair.
- BRCA1 R1699Q abrogates the repression of miR-155.
- BRCA1 epigenetically represses miR-155 via HDAC2-mediated deacetylation of histones on the miR-155 promoter.
- miR-155 overexpression accelerates tumor cell growth, while knockdown attenuates it.
Conclusions:
- BRCA1 exhibits a novel tumor suppressive function through epigenetic repression of miR-155.
- The R1699Q variant disrupts this function, highlighting its oncogenic potential.
- miR-155 is a potential therapeutic target for BRCA1-deficient tumors.
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