Abstract
The MYC oncogenes encode a family of transcription factors that feature prominently in cancer. MYC proteins are overexpressed or deregulated in a majority of malignancies and drive tumorigenesis by inducing widespread transcriptional reprogramming that promotes cell proliferation, metabolism, and genomic instability. The ability of MYC to regulate transcription depends on its dimerization with MAX, which creates a DNA-binding domain that recognizes specific sequences in the regulatory elements of MYC target genes. Recently, we discovered that recognition of target genes by MYC also depends on its interaction with WDR5, a WD40-repeat protein that exists as part of several chromatin-regulatory complexes. Here, we discuss how interaction of MYC with WDR5 could create an avidity-based chromatin recognition mechanism that allows MYC to select its target genes in response to both genetic and epigenetic determinants. We rationalize how the MYC-WDR5 interaction provides plasticity in target gene selection by MYC and speculate on the biochemical and genomic contexts in which this interaction occurs. Finally, we discuss how properties of the MYC-WDR5 interface make it an attractive point for discovery of small-molecule inhibitors of MYC function in cancer cells.
©2015 American Association for Cancer Research.
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
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Chromatin Assembly and Disassembly / genetics
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Chromatin Assembly and Disassembly / physiology*
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DNA / genetics
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DNA / metabolism
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DNA Methylation
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Drug Discovery
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Epigenesis, Genetic
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology*
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Genes, myc
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / physiology*
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Histones / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Models, Genetic
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Molecular Targeted Therapy
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasms / drug therapy
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Neoplasms / genetics*
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Protein Binding
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / physiology*
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Repressor Proteins / physiology*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Histones
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Intracellular Signaling Peptides and Proteins
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MXD1 protein, human
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Neoplasm Proteins
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Proto-Oncogene Proteins c-myc
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Repressor Proteins
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WDR5 protein, human
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DNA
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Histone-Lysine N-Methyltransferase