Related Experiment Video

Updated: Mar 19, 2026

Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
11:13

Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment

Published on: June 9, 2023

2.5K

PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer

Jennifer M Spangle1, Koen M Dreijerink2, Anna C Groner2

  • 1Department 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.

Cell Reports
|June 14, 2016
PubMed

Insights

Activating PIK3CA signaling increases H3K4me3 in breast tumors. PI3K/AKT pathway inhibition reduces this mark by targeting KDM5A, a histone demethylase, revealing a new epigenetic mechanism in cancer.

Area of Science:

  • Epigenetics
  • Molecular Oncology
  • Cancer Biology

Background:

  • Post-translational histone modifications, particularly histone H3 modifications, are crucial regulators of gene transcription.
  • The precise mechanisms governing epigenome regulation in response to oncogenic signaling, such as that driven by PIK3CA, are not fully understood.
  • Understanding these mechanisms is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the role of PI3K/AKT signaling in regulating histone H3 lysine 4 trimethylation (H3K4me3) in breast cancer.
  • To investigate the involvement of the H3K4 demethylase KDM5A in mediating the transcriptional effects of PI3K/AKT signaling.
  • To identify potential pharmacodynamic markers for PI3K/AKT inhibitors.

Main Methods:

  • Analysis of H3K4me3 levels in breast tumors with activated PIK3CA.
  • Assessment of PI3K/AKT signaling inhibition on promoter-associated H3K4me3 in human breast cancer cells.
  • Investigation of KDM5A as an AKT target, including its phosphorylation, nuclear localization, and promoter occupancy.
  • Evaluation of KDM5A's role in regulating cell-cycle gene expression upon AKT inhibition using KDM5A silencing.

Main Results:

  • H3K4me3 is elevated in breast tumors driven by activated PIK3CA.
  • Inhibition of PI3K/AKT signaling leads to a reduction in promoter-associated H3K4me3 in breast cancer cells.
  • KDM5A was identified as a direct AKT target, with its phosphorylation regulating its subcellular localization and promoter binding.
  • Silencing KDM5A partially reversed the effect of AKT inhibition on the expression of specific cell-cycle genes linked to poor clinical outcomes.

Conclusions:

  • PI3K/AKT signaling modulates the cancer epigenome by controlling H3K4 methylation, with KDM5A playing a key role.
  • KDM5A's subcellular localization and genome occupancy serve as potential pharmacodynamic biomarkers for assessing PI3K/AKT inhibitor activity.
  • This study reveals a novel epigenetic regulatory mechanism in cancer driven by PI3K/AKT signaling.

More Related Videos

Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark10:09

Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark

Published on: January 26, 2018

8.0K
Methyl-binding DNA capture Sequencing for Patient Tissues08:40

Methyl-binding DNA capture Sequencing for Patient Tissues

Published on: October 31, 2016

9.1K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.6K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.8K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
13.7K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
4.1K