Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase
- Xingnan Zheng1,
- Bo Zhai2,
- Peppi Koivunen3,
- Sandra J. Shin4,
- Gang Lu5,
- Jiayun Liu5,
- Christoph Geisen5,
- Abhishek A. Chakraborty5,
- Javid J. Moslehi5,
- David M. Smalley6,
- Xin Wei7,
- Xian Chen7,
- Zhengming Chen8,
- Justine M. Beres1,
- Jing Zhang1,
- Jen Lan Tsao9,
- Mitchell C. Brenner9,
- Yuqing Zhang4,
- Cheng Fan1,
- Ronald A. DePinho10,
- Jihye Paik4,
- Steven P. Gygi2,
- William G. Kaelin Jr.5,11,13 and
- Qing Zhang1,12,13
- 1Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
- 2Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland;
- 4Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
- 5Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
- 6Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
- 7Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
- 8Department of Public Health, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, New York 10065, USA;
- 9Fibrogen, Incorporated, San Francisco, California 94158, USA;
- 10Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 11Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;
- 12Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
Abstract
The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.
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Footnotes
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↵13 Corresponding authors
E-mail qing_zhang{at}med.unc.edu
E-mail william_kaelin{at}dfci.harvard.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.242131.114.
- Received March 24, 2014.
- Accepted May 29, 2014.
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