期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 43, 页码 17284-17289出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1307959110
关键词
ER alpha hinge region; lysine methylation; LSD1
资金
- American Cancer Society [RSG-13-290-01-TBE]
- Cancer Prevention Research Institute of Texas [RP110471]
- Welch [G1719]
- National Institutes of Health/MD Anderson
- Cancer Center [CA016672]
- MDA Institutional Research Grant
- Leukemia Research Foundation
- Aplastic Anemia & Myelodysplastic Syndromes International Foundation
- MDA Center for Cancer Epigenetics Postdoc Scholar Award
- Kimmel Scholar Award
Estrogen receptor alpha (ER alpha) is a ligand-activated transcription factor. Upon estrogen stimulation, ER alpha recruits a number of coregulators, including both coactivators and corepressors, to the estrogen response elements, modulating gene activation or repression. Most coregulator complexes contain histone-modifying enzymes to control ER alpha target gene expression in an epigenetic manner. In addition to histones, these epigenetic modifiers can modify nonhistone proteins including ER alpha, thereby constituting another layer of transcriptional regulation. Here we show that SET and MYND domain containing 2 (SMYD2), a histone H3K4 and H3K36 methyltransferase, directly methylates ER alpha protein at lysine 266 (K266) both in vitro and in cells. In breast cancer MCF7 cells, SMYD2 attenuates the chromatin recruitment of ER alpha to prevent ER alpha target gene activation under an estrogen-depleted condition. Importantly, the SMYD2-mediated repression of ER alpha target gene expression is mediated by the methylation of ER alpha at K266 in the nucleus, but not the methylation of histone H3K4. Upon estrogen stimulation, ER alpha-K266 methylation is diminished, thereby enabling p300/cAMP response element-binding protein-binding protein to acetylate ER alpha at K266, which is known to promote ERa transactivation activity. Our study identifies a previously undescribed inhibitory methylation event on ER alpha. Our data suggest that the dynamic cross-talk between SMYD2-mediated ER alpha protein methylation and p300/cAMP response element-binding protein-binding protein-dependent ER alpha acetylation plays an important role in fine-tuning the functions of ER alpha at chromatin and the estrogen-induced gene expression profiles.
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