title: The adenoviral E1A N-terminal domain represses MYC transcription in human cancer cells by targeting both p300 and TRRAP and inhibiting MYC promoter acetylation of H3K18 and H4K16.
abstract: Human cancers frequently arise from increased expression of proto-oncogenes, such as MYC and HER2. Understanding the cellular pathways regulating the transcription and expression of proto-oncogenes is important for targeted therapies for cancer treatment. Adenoviral (Ad) E1A 243R (243 aa residues) is a viral oncoprotein that interacts with key regulators of gene transcription and cell proliferation. We have shown previously that the 80 amino acid N-terminal transcriptional repression domain of E1A 243R (E1A 1-80) can target the histone acetyltransferase (HAT) p300 and repress HER2 in the HER2-overexpressing human breast cancer cell line SKBR3. Expression of E1A 1-80 induces death of SKBR3 and other cancer cell lines. In this study, we performed total cell RNA sequence analysis and identified MYC as the regulatory gene for cellular proliferation most strongly repressed by E1A 1-80. By RT-quantitative PCR analysis we show that repression of MYC in SKBR3 cells occurs early after expression of E1A 1-80, suggesting that MYC may be an early responder of E1A 1-80-mediated transcriptional repression. Of interest, while E1A 1-80 repression of MYC occurs in all eight human cancer cell lines examined, repression of HER2 is cell-type dependent. We demonstrate by ChIP analysis that MYC transcriptional repression by E1A 1-80 is associated with inhibition of acetylation of H3K18 and H4K16 on the MYC promoter, as well as inhibition of RNA Pol II binding to the MYC promoter. Deletion mutant analysis of E1A 1-80 suggests that both p300/CBP and TRRAP are involved in E1A 1-80 repression of MYC transcription. Further, E1A 1-80 interaction with p300/CBP and TRRAP is correlated with inhibition of H3K18 and H4K16 acetylation on the MYC promoter, respectively. Our results indicate that E1A 1-80 may target two important pathways for histone modification to repress transcription in human cancer cells.
authors.affiliation: Institute for Molecular Virology, Department of Microbiology and Molecular Immunology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, Missouri, USA.
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Zhao
authors.affiliation: Institute for Molecular Virology, Department of Microbiology and Molecular Immunology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, Missouri, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loewenstein
authors.affiliation: Institute for Molecular Virology, Department of Microbiology and Molecular Immunology, Saint Louis University School of Medicine, Doisy Research Center, St. Louis, Missouri, USA.
authors.forename: Maurice
authors.initials: M
authors.lastname: Green
keywords: H3K18Ac; H4K16Ac; HER2; MYC; TRRAP; adenoviral E1A 1-80; p300/CBP; transcriptional repression