A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression.
Austin G HolmesJ Brandon ParkerVinay SagarMihai Ioan TruicaPritin N SoniHuiying HanGary E SchiltzSarki A AbdulkadirDebabrata ChakravartiPublished in: Science advances (2022)
MYC regulates multiple gene programs, raising questions about the potential selectivity and downstream transcriptional consequences of MYC inhibitors as cancer therapeutics. Here, we examined the effect of a small-molecule MYC inhibitor, MYCi975, on the MYC/MAX cistromes, epigenome, transcriptome, and tumorigenesis. Integrating these data revealed three major classes of MYCi975-modulated gene targets: type 1 (down-regulated), type 2 (up-regulated), and type 3 (unaltered). While cell cycle and signal transduction pathways were heavily targeted by MYCi, RNA biogenesis and core transcriptional pathway genes were spared. MYCi975 altered chromatin binding of MYC and the MYC network family proteins, and chromatin accessibility and H3K27 acetylation alterations revealed MYCi975 suppression of MYC-regulated lineage factors AR/ARv7, FOXA1, and FOXM1. Consequently, MYCi975 synergistically sensitized resistant prostate cancer cells to enzalutamide and estrogen receptor-positive breast cancer cells to 4-hydroxytamoxifen. Our results demonstrate that MYCi975 selectively inhibits MYC target gene expression and provide a mechanistic rationale for potential combination therapies.
Keyphrases
- transcription factor
- gene expression
- genome wide
- genome wide identification
- small molecule
- dna methylation
- cell cycle
- dna binding
- single cell
- estrogen receptor
- prostate cancer
- dna damage
- cell proliferation
- public health
- breast cancer cells
- squamous cell carcinoma
- machine learning
- young adults
- electronic health record
- deep learning
- binding protein
- cancer therapy
- squamous cell