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DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia
Author(s) -
Ricci Anastasia,
Galluzzi Luca,
Magnani Mauro,
Menotta Michele
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902039r
Subject(s) - hdac4 , downregulation and upregulation , neurodegeneration , ataxia telangiectasia , dexamethasone , hdac6 , cancer research , histone deacetylase , cockayne syndrome , transcription factor , ataxia , microbiology and biotechnology , histone , medicine , biology , gene , neuroscience , endocrinology , genetics , disease , dna damage , dna repair , dna , nucleotide excision repair
Ataxia telangiectasia (AT) is a rare, severe, and ineluctably progressive multisystemic neurodegenerative disease. Histone deacetylase 4 (HDAC4) nuclear accumulation has been related to neurodegeneration in AT. Since treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome, the effects of dexamethasone on HDAC4 were investigated. In this paper, we describe a novel nonepigenetic function of HDAC4 induced by dexamethasone, through which it can directly modulate HIF‐1a activity and promote the upregulation of the DDIT4 gene and protein expression. This new HDAC4 transcription regulation mechanism leads to a positive effect on autophagic flux, an AT‐compromised biological pathway. This signaling was specifically induced by dexamethasone only in AT cell lines and can contribute in explaining the positive effects of dexamethasone observed in AT‐treated patients.