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Abstract
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.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00755-15.
ACKNOWLEDGMENTS
We thank the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) for providing the transgenic RNAi fly stocks used in this study. We thank Didier Trouche and members of the LBCMCP and of the Dyson laboratory for technical assistance and helpful discussion.
This work was supported by National Institutes of Public Health Service grants R01 CA163698 and R01 CA64402 to N.J.D. and by the Fondation pour la Recherche Médicale (FRM AJE201109), the Agence Nationale de la Recherche (ANR 2012-CHEX-0002-01), a Marie Curie Career Integration Grant (PCIG13-GA-2013-618272), and the Région Midi-Pyrénées (reference 13051317) to L.D.S. N.J.D. is the James and Shirley Curvey MGH Research Scholar. J.M.J.L. is supported by a postdoctoral fellowship from the Association de la Recherche sur le Cancer.
We declare that we have no conflicts of interest.