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Nat Commun. 2017 Mar 16;8:14799. doi: 10.1038/ncomms14799.

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis.

Zhang X1,2,3, Li B2, Rezaeian AH2, Xu X2, Chou PC1,2, Jin G1,2, Han F1,2,3, Pan BS1,2, Wang CY1,2, Long J1,2, Zhang A1,2, Huang CY4,5, Tsai FJ6,7, Tsai CH5,8, Logothetis C9, Lin HK1,2,3,4,5.

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Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.
Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
Department of Medical Genetics, Pediatrics and Medical Research, China Medical University Hospital, Taichung 40402, Taiwan.
Center of Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.


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.

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