Abstract
Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer. Identification of new histone marks critical for cancer development is of particular importance. Here we show that, in a glucose-dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on lysine 23/36/37 residues, which specifically recruits histone acetyltransferase GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing reveals that NEDD4 regulates glucose-induced H3 K9 acetylation at transcription starting site and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent role of NEDD4 in transcription activation and H3 K9 acetylation in response to glucose. Functionally, we show that NEDD4-mediated H3 ubiquitination, by transcriptionally activating IL1α, IL1β and GCLM, is important for tumour sphere formation. Together, our study reveals the mechanism for glucose-induced transcriptome reprograming and epigenetic regulation in cancer by inducing NEDD4-dependent H3 ubiquitination.
Highlights
Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer
H3 ubiquitination is regulated by the glucose status, we found that H3 ubiquitination is not affected by cell cycle (Supplementary Fig. 1d)
Glucose treatment on glucose-starved cells elevated cellular calcium level, which is associated with NEDD4 E3 ligase activation, providing an explanation why H3 ubiquitination is enhanced by glucose treatment
Summary
Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer. Stress-sensing machinery in the cell transduces environmental changes to cellular signalling and activated signalling cascade eventually triggers the histone modification machinery to regulate gene transcription[5]. Environmental changes such as metabolism-related changes have been shown to affect histone modification directly, as many metabolic intermediates are co-factors or substrates for the enzymatic reaction of histone modification[6]. Ubiquitination modification ranges from mono, poly or even multi-mono, multi-polyubiquitination, which decide the distinct fate of the proteins, including proteasomal degradation, lysosomal degradation or protein trafficking[11] Histones such as histone H2A and H2B are well known to be ubiquitinated and their ubiquitination cross-talks with other histone modifications and regulates gene transcription[12]. Cellular Ca2 þ , which binds to NEDD4 C2 domain, or phosphorylation at both domains, could disrupt the self-inhibitory structure and activate NEDD4 E3 ligase activity[16,17]
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