PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer

• Published in: Cell reports (Cambridge) Vol. 15; no. 12; pp. 2692 - 2704
• Main Authors: Spangle, Jennifer M., Dreijerink, Koen M., Groner, Anna C., Cheng, Hailing, Ohlson, Carolynn E., Reyes, Jaime, Lin, Charles Y., Bradner, James, Zhao, Jean J., Roberts, Thomas M., Brown, Myles
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.06.2016; Elsevier
• Subjects: Amino Acid Sequence; Animals; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle - genetics; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Histones - metabolism; Humans; Lysine - metabolism; Methylation; Mice; Models, Biological; Phosphatidylinositol 3-Kinases - metabolism; Promoter Regions, Genetic; Protein Transport; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Retinoblastoma-Binding Protein 2 - chemistry; Retinoblastoma-Binding Protein 2 - metabolism; Subcellular Fractions - enzymology; Substrate Specificity; Treatment Outcome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.046

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. [Display omitted] •PI3K/AKT pathway activation increases H3K4 trimethylation in models of breast cancer•AKT phosphorylates the H3K4-demethylase KDM5A and directs it to the cytoplasm•AKT and KDM5A cooperate to regulate the expression of cell-cycle genes•Expression of AKT/KDM5A-regulated genes is associated with advanced-stage breast cancer Spangle et al. report that PI3K/AKT pathway activation increases H3K4 trimethylation in preclinical models of breast cancer. They show that the H3K4 demethylase KDM5A is an AKT target that cooperates with AKT to increase the expression of cell-cycle genes associated with advanced-stage breast cancer.