Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes.

Autor:	Moody RR; From the Chemical Biology Program.; Department of Pharmaceutical Sciences, College of Pharmacy., Lo MC; Department of Pharmaceutical Sciences, College of Pharmacy, miaoclo@umich.edu., Meagher JL; Life Sciences Institute, and., Lin CC; Department of Pharmaceutical Sciences, College of Pharmacy., Stevers NO; Department of Pharmaceutical Sciences, College of Pharmacy., Tinsley SL; Department of Pharmaceutical Sciences, College of Pharmacy., Jung I; Department of Pharmaceutical Sciences, College of Pharmacy., Matvekas A; Department of Pharmaceutical Sciences, College of Pharmacy., Stuckey JA; Life Sciences Institute, and.; Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109., Sun D; From the Chemical Biology Program, duxins@umich.edu.; Department of Pharmaceutical Sciences, College of Pharmacy.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2018 Feb 09; Vol. 293 (6), pp. 2125-2136. Date of Electronic Publication: 2017 Dec 20.
DOI:	10.1074/jbc.M117.811463
Abstrakt:	The transcription factor BCL11A has recently been reported to be a driving force in triple-negative breast cancer (TNBC), contributing to the maintenance of a chemoresistant breast cancer stem cell (BCSC) population. Although BCL11A was shown to suppress γ-globin and p21 and to induce MDM2 expression in the hematopoietic system, its downstream targets in TNBC are still unclear. For its role in transcriptional repression, BCL11A was found to interact with several corepressor complexes; however, the mechanisms underlying these interactions remain unknown. Here, we reveal that BCL11A interacts with histone methyltransferase (PRC2) and histone deacetylase (NuRD and SIN3A) complexes through their common subunit, RBBP4/7. In fluorescence polarization assays, we show that BCL11A competes with histone H3 for binding to the negatively charged top face of RBBP4. To define that interaction, we solved the crystal structure of RBBP4 in complex with an N-terminal peptide of BCL11A (residues 2-16, BCL11A(2-16)). The crystal structure identifies novel interactions between BCL11A and the side of the β-propeller of RBBP4 that are not seen with histone H3. We next show that BCL11A(2-16) pulls down RBBP4, RBBP7, and other components of PRC2, NuRD, and SIN3A from the cell lysate of the TNBC cell line SUM149. Furthermore, we demonstrate the therapeutic potential of targeting the RBBP4-BCL11A binding by showing that a BCL11A peptide can decrease aldehyde dehydrogenase-positive BCSCs and mammosphere formation capacity in SUM149. Together, our findings have uncovered a previously unidentified mechanism that BCL11A may use to recruit epigenetic complexes to regulate transcription and promote tumorigenesis. Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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