MYC regulates multiple gene programs, raising questions about the potential selectivity and downstream transcriptional consequences of MYC inhibitors as cancer therapeutics. MYC func-tions to either globally amplify RNA production or selectively regulates genes by repression or ac-tivation. In models of MYC inhibition by small molecules the functionality of MYC is greatly reduced although specific MYC function may be more sensitive than others. Here, we examined the effect of a small molecule MYC inhibitor, MYCi975, on the MYC/MAX cistromes, epigenome, transcriptome and tumorigenesis. These data revealed three major classes of MYCi975-modulated gene targets: Type 1 (downregulated), Type 2 (upregulated) and Type 3 (unaltered). While cell cycle and signal transduction pathways were heavily targeted by MYCi975, RNA biogenesis and core transcriptional pathway genes were spared. MYCi975 altered chromatin binding of MYC, and the MYC network family proteins including MAX and MAX heterodimeric binding partners. Both genome-wide chromatin accessibility and H3K27-acetylation was altered by MYCi975, and motif analysis revealed enrichment of MYC-regulated lineage factors AR/ARv7, FOXA1 and FOXM1. Subsequently, chromatin occupancy analysis following MYCi975 treatment demonstrat-ed loss of lineage factors overlapping differential chromatin accessibility and H3K27ac sites. Consequently, MYCi975 synergistically sensitized resistant prostate cancer cells to enzalutamide and estrogen receptor positive breast cancer cells to 4-hydroxytamoxifen. Although MYC inhibition induced a loss of chromatin occupancy and expression of many transcription factors, the MYCi975 activated cistrome has yet to be elucidated. MYCi975 induced ATF4 protein stability and downstream ATF4 signaling promoting apoptosis. Using MYC knockdown and knockout models we determined that MYCi975 induction of ATF4 is dependent on MYC expression levels however MYC canonically functions to regulate ATF4 induction. These results demonstrate that MYCi975 selectively inhibits MYC target gene expression and provide a mechanistic rationale for potential combination therapies.

Creator

• Holmes, Austin Gable

DOI

• https://doi.org/10.21985/n2-y08a-ns06

Subject

• Molecular biology
• Biochemistry

Language

• en

Alternate Identifier

• etdadmin_upload_904142
• http://dissertations.umi.com/northwestern:16111

Date created

• 2022-01-01

Resource type

• Dissertation

Rights statement

• In Copyright