TY - JOUR
T1 - Histone signatures predict therapeutic efficacy in breast cancer
AU - Mollah, Shamim A.
AU - Subramaniam, Shankar
N1 - Publisher Copyright:
© 2020 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission. See https://www.ieee.org/publications/rights/index.html for more information.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - BRD4
KW - Breast cancer
KW - Chromatin remodeling
KW - Flavopiridol
KW - Histone modification
UR - http://www.scopus.com/inward/record.url?scp=85109406636&partnerID=8YFLogxK
U2 - 10.1109/OJEMB.2020.2967105
DO - 10.1109/OJEMB.2020.2967105
M3 - Article
C2 - 32412527
AN - SCOPUS:85109406636
SN - 2644-1276
VL - 1
SP - 74
EP - 82
JO - IEEE Open Journal of Engineering in Medicine and Biology
JF - IEEE Open Journal of Engineering in Medicine and Biology
M1 - 8961959
ER -