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Updated: Dec 21, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone Signatures Predict Therapeutic Efficacy in Breast Cancer
Shamim A Mollah1, Shankar Subramaniam2
111Bioinformatics & Systems Biology ProgramThe University of California San DiegoLa JollaCA92093USA.
Abstract:
Objective: Regulatory abnormalities caused by chromatin modifications are being increasingly recognized as contributors to cancer. While many molecularly targeted drugs have the potential to revert these modifications, their precise mechanism of action in cellular reprogramming is not known. Methods: To address this, we introduce an integrated phosphoprotein-histone-drug network (iPhDNet) approach to generate "global chromatin fingerprints of histone signatures." The method integrates proteomic/phosphoproteomic, transcriptomic and regulatory genomic data to provide a causal mechanistic network and histone signatures of drug response. Results: We demonstrate the utility of iPhDNet in identifying H3K27me3K36me3 histone mark as a key fingerprint of response, mediated by chromatin remodelers BRD4, NSD3, EZH2, and a proto-oncogene MYC when treated with CDK inhibitors. Conclusions: We construct a regulatory network of breast cancer response to treatment and show that histone H3K27me3K36me3 status changes, driven by the BRD4/MYC pathway, upon treatment with drugs are hallmarks of response to treatment.
Insights
This study reveals a new method to understand how cancer drugs reprogram cells by analyzing chromatin modifications. The findings highlight specific histone marks and proteins involved in treatment response.
Area of Science:
- Oncology
- Epigenetics
- Systems Biology
Background:
- Chromatin modifications are increasingly implicated in cancer development.
- The precise mechanisms by which targeted drugs reprogram cells via chromatin modification remain unclear.
Purpose of the Study:
- To develop a novel computational approach for understanding drug mechanisms in cancer.
- To identify key molecular players and epigenetic signatures associated with therapeutic response.
Main Methods:
- Development of an integrated phosphoprotein-histone-drug network (iPhDNet) approach.
- Integration of multi-omics data: proteomic, phosphoproteomic, transcriptomic, and regulatory genomics.
- Generation of "global chromatin fingerprints of histone signatures".
Main Results:
- Identification of H3K27me3K36me3 histone mark as a critical response fingerprint.
- Demonstration of mediation by chromatin remodelers (BRD4, NSD3, EZH2) and MYC.
- Characterization of response to CDK inhibitors in breast cancer models.
Conclusions:
- Construction of a regulatory network for breast cancer treatment response.
- Histone H3K27me3K36me3 status changes, driven by the BRD4/MYC pathway, are hallmarks of drug response.
- The iPhDNet approach provides mechanistic insights into cellular reprogramming by targeted therapies.
