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AURKB, in concert with REST, acts as an oxygen-sensitive epigenetic regulator of the hypoxic induction of MDM2
Iljin Kim1,# (Professor), Sanga Choi1,# (Graduate student), Seongkyeong Yoo1 (Graduate student), Mingyu Lee2 (Research worker), Jong-Wan Park 3,4,* (Professor)
1Pharmacology, Inha University College of Medicine,
2Medicine, Brigham and Women's Hospital, Harvard Medical School,
3Pharmacology, Seoul National University College of Medicine,
4Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine
Abstract
The acute response to hypoxia is mainly driven by hypoxia-inducible factors, but their effects gradually subside with time. Hypoxia-specific histone modifications may be important for the stable maintenance of long-term adaptation to hypoxia. However, little is known about the molecular mechanisms underlying the dynamic alterations of histones under hypoxic conditions. We found that the phosphorylation of histone H3 at Ser-10 (H3S10) was noticeably attenuated after hypoxic challenge, which was mediated by the inhibition of aurora kinase B (AURKB). To understand the role of AURKB in epigenetic regulation, DNA microarray and transcription factor binding site analyses combined with proteomics analysis were performed. Under normoxia, phosphorylated AURKB, in concert with the repressor element-1 silencing transcription factor (REST), phosphorylates H3S10, which allows the AURKB–REST complex to access the MDM2 proto-oncogene. REST then acts as a transcriptional repressor of MDM2 and downregulates its expression. Under hypoxia, AURKB is dephosphorylated and the AURKB–REST complex fails to access MDM2, leading to the upregulation of its expression. In this study, we present a case of hypoxia-specific epigenetic regulation of the oxygen-sensitive AURKB signaling pathway. To better understand the cellular adaptation to hypoxia, it is worthwhile to further investigate the epigenetic regulation of genes under hypoxic conditions.
Abstract, Accepted Manuscript(in press) [Submitted on January 26, 2022, Accepted on April 8, 2022]
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