The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop

The lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors, and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expr...

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Bibliographic Details
Published in:Molecular and cellular biology 2015-12, Vol.35 (24), p.4199-4211
Main Authors: Miles, Wayne O., Lepesant, Julie M. J., Bourdeaux, Jessie, Texier, Manuela, Kerenyi, Marc A., Nakakido, Makoto, Hamamoto, Ryuji, Orkin, Stuart H., Dyson, Nicholas J., Di Stefano, Luisa
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
DNA-Binding Proteins - biosynthesis
Drosophila
Drosophila Proteins - biosynthesis
Drosophila Proteins - metabolism
Feedback, Physiological
HeLa Cells
Histone Demethylases - metabolism
Humans
MCF-7 Cells
Mice
Oxidoreductases, N-Demethylating - metabolism
RNA Interference
RNA Processing, Post-Transcriptional
RNA, Messenger - genetics
RNA, Small Interfering
RNA-Binding Proteins - biosynthesis
RNA-Binding Proteins - metabolism
Urinary Bladder Neoplasms - pathology
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Summary:The lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors, and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expression of the Pumilio (PUM) translational repressor complex enhanced phenotypes due to dLsd1 depletion in Drosophila . We show that the PUM complex is a target of LSD1 regulation in fly and mammalian cells and that its expression is inversely correlated with LSD1 levels in human bladder carcinoma. Unexpectedly, we find that PUM posttranscriptionally regulates LSD1 family protein levels in flies and human cells, indicating the existence of feedback loops between the LSD1 family and the PUM complex. Our results highlight a new posttranscriptional mechanism regulating LSD1 activity and suggest that the feedback loop between the LSD1 family and the PUM complex may be functionally important during development and in human malignancies.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00755-15