A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression

Austin G. Holmes, J. Brandon Parker, Vinay Sagar, Mihai I. Truica, Pritin N. Soni, Huiying Han, Gary E. Schiltz, Sarki A. Abdulkadir, Debabrata Chakravarti

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)eabh3635
JournalScience Advances
Volume8
Issue number17
DOIs
StatePublished - Apr 29 2022

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'A MYC inhibitor selectively alters the MYC and MAX cistromes and modulates the epigenomic landscape to regulate target gene expression'. Together they form a unique fingerprint.

Cite this