The Novel Regulation of Histone Modification In Cancer Development

<p>Dynamic changes in histone acetylation by various physiological cues play important roles in gene transcription and cancer. However, the cellular signaling underlying this regulation is not well understood. Here, we show that, in a glucose dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on previously unstudied lysine (K) 23/36/37 residues, which specifically recruits histone acetyltransferase (HAT) GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets reveals that NEDD4 regulates glucose-induced H3K9 acetylation at transcription starting site (TSS) and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent role of H3 ubiquitination in transcription activation and H3 K9 acetylation in response to glucose. Functionally, we showed that NEDD4-mediated H3 ubiquitination is critical for tumorigenesis and that IL1A, IL1B and GCLM are important target genes to elicit the function of glucose-induced H3 ubiquitination in tumor sphere formation. Together, our study provides a new model for glucose-induced transcriptome reprograming and epigenetic regulation in cancer through inducing NEDD4-dependent H3 ubiquitination.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Author dc:creator

• zhang, xian

Contributors dc:contributor

• Hui-Kuan Lin
• Min Gyu Lee
• Jianping Jin

• H3 ubiquitination
• Nedd4 and cancer stem cells
• H3 acetylation by glucose
• Life Sciences
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/675

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1718