title: Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
authors.forename: Xingnan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland;
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
authors.forename: Jiayun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
authors.forename: Christoph
authors.initials: C
authors.lastname: Geisen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
authors.forename: Abhishek A
authors.initials: AA
authors.lastname: Chakraborty
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA;
authors.forename: Javid J
authors.initials: JJ
authors.lastname: Moslehi
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
authors.forename: David M
authors.initials: DM
authors.lastname: Smalley
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Public Health, Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, New York 10065, USA;
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
authors.forename: Justine M
authors.initials: JM
authors.lastname: Beres
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Fibrogen, Incorporated, San Francisco, California 94158, USA;
authors.forename: Jen Lan
authors.initials: JL
authors.lastname: Tsao
authors.affiliation: Fibrogen, Incorporated, San Francisco, California 94158, USA;
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Brenner
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA;
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
authors.forename: Jihye
authors.initials: J
authors.lastname: Paik
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006900:Hydroxylation; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D011485:Protein Binding; D055550:Protein Stability; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019938:Cyclin D1; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D043222:Ubiquitin Thiolesterase
keywords: Cyclin D1; EglN2; FOXO3a; USP9x; breast cancer; prolyl hydroxylation