Chromatin Biology and Cancer Linked Through Protein–Protein Interactions
Up-to-date human protein–protein interaction (PPI) networks for chromatin modification (CM) proteins are constructed and analyzed to explore the functional link between cancer and chromatin-modifying enzymes (CME), such as histone acetyltransferases (HAT), histone deacetylases (HDAC), histone methyltransferases (HMT), histone demethylases (HDM), and DNA-modifying enzymes (DME, including DNA methyltransferases and methylcytosine dioxygenases). In a high-confidence human CM network, extensive interactions (physical associations) are found among CMEs, indicating that CMEs regulate and cooperate with each other to produce complex epigenetic marks. Our results also show that neighbors (interaction partners) of CMEs are enriched not only with proteins involved in transcription (transcription factors and cofactors) but also with proteins coded by oncogenes, tumor suppressor genes, and cancer genes. It is highly likely that products of oncogenes and tumor suppressor genes control gene expression at least in part by regulating the activities of CMEs and that dys-regulation of CMEs plays an important role in tumorigenesis. In addition to drugs targeting CMEs and chromatin readers, drugs targeting process-specific regulators (activators, inhibitors, and recruiters) of CMEs may provide effective and selective alternatives for epigenetic cancer therapy. Identification and characterization of CME regulators should be a top priority in epigenetics and cancer research.
KeywordsChromatin modification Protein–protein interaction Transcription Tumor suppressor Oncogene Cancer Epigenetic therapy
We thank Andrew Emili, Jack Greenblatt, Michael Tyers, John Parkinson, and Zhaolei Zhang as well as members of their teams for many fruitful discussions. We gratefully acknowledge support by the Canadian Institutes of Health Research [MOP#82940], the Ontario Research Fund Global Leadership Program, and the SickKids Foundation. SJW was Canada Research Chair, Tier 1, funded by the Canada Institute of Health Research.
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