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PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.
- Source :
-
Science (New York, N.Y.) [Science] 2017 Mar 24; Vol. 355 (6331), pp. 1324-1330. - Publication Year :
- 2017
-
Abstract
- Activating mutations in PIK3CA , the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.<br /> (Copyright © 2017, American Association for the Advancement of Science.)
- Subjects :
- Animals
Chromatin metabolism
Class I Phosphatidylinositol 3-Kinases genetics
DNA-Binding Proteins genetics
Female
HEK293 Cells
Hepatocyte Nuclear Factor 3-alpha genetics
Hepatocyte Nuclear Factor 3-alpha metabolism
Humans
Lysine genetics
Lysine metabolism
MCF-7 Cells
Metabolic Networks and Pathways
Methyltransferases genetics
Mice
Mice, Nude
Neoplasm Proteins genetics
Pre-B-Cell Leukemia Transcription Factor 1
Protein Processing, Post-Translational
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Receptors, Estrogen genetics
Breast Neoplasms genetics
Breast Neoplasms therapy
Class I Phosphatidylinositol 3-Kinases metabolism
DNA-Binding Proteins metabolism
Epigenesis, Genetic
Methyltransferases metabolism
Neoplasm Proteins metabolism
Receptors, Estrogen metabolism
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 355
- Issue :
- 6331
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 28336670
- Full Text :
- https://doi.org/10.1126/science.aah6893