PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer.
Post-translational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show that H3K4me3 is increased in breast tumors driven by an activated PIK3CA allele and that inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy. Supporting a role for KDM5A in mediating PI3K/AKT transcriptional effects, the decreased expression in response to AKT inhibition of a subset of cell-cycle genes associated with poor clinical outcome is blunted by KDM5A silencing. Our data identify a mechanism by which PI3K/AKT signaling modulates the cancer epigenome through controlling H3K4 methylation and suggest that KDM5A subcellular localization and genome occupancy may be pharmacodynamic markers of the activity of PI3K/AKT inhibitors currently in clinical development.
Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Jennifer M
JM
Spangle
Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA.
Koen M
KM
Dreijerink
Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA.
Anna C
AC
Groner
Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Hailing
H
Cheng
Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Carolynn E
CE
Ohlson
Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA.
Jaime
J
Reyes
Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA.
Charles Y
CY
Lin
Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA.
James
J
Bradner
Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Jean J
JJ
Zhao
Department of Cancer Biology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. Electronic address: thomas_roberts@dfci.harvard.edu.
Thomas M
TM
Roberts
Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA. Electronic address: myles_brown@dfci.harvard.edu.
Myles
M
Brown
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056485:Retinoblastoma-Binding Protein 2 / Q000737:chemistry / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D013379:Substrate Specificity; D016896:Treatment Outcome
D006657:Histones; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine