A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies

Daichi Inoue, Takeshi Fujino, Paul Sheridan, Yao Zhong Zhang, Reina Nagase, Sayuri Horikawa, Zaomin Li, Hirotaka Matsui, Akinori Kanai, Makoto Saika, Rui Yamaguchi, Hiroko Kozuka-Hata, Kimihito Cojin Kawabata, Akihiko Yokoyama, Susumu Goyama, Toshiya Inaba, Seiya Imoto, Satoru Miyano, Mingjiang Xu, Feng Chun YangMasaaki Oyama, Toshio Kitamura

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that ML5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.

Original languageEnglish (US)
Pages (from-to)1327-1337
Number of pages11
JournalLeukemia
Volume32
Issue number6
DOIs
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Inoue, D., Fujino, T., Sheridan, P., Zhang, Y. Z., Nagase, R., Horikawa, S., Li, Z., Matsui, H., Kanai, A., Saika, M., Yamaguchi, R., Kozuka-Hata, H., Kawabata, K. C., Yokoyama, A., Goyama, S., Inaba, T., Imoto, S., Miyano, S., Xu, M., ... Kitamura, T. (2018). A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia, 32(6), 1327-1337. https://doi.org/10.1038/s41375-018-0083-3