Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.

TitleProlyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.
Publication TypeJournal Article
Year of Publication2014
AuthorsZheng X, Zhai B, Koivunen P, Shin SJ, Lu G, Liu J, Geisen C, Chakraborty AA, Moslehi JJ, Smalley DM, Wei X, Chen X, Chen Z, Beres JM, Zhang J, Tsao JLan, Brenner MC, Zhang Y, Fan C, DePinho RA, Paik J, Gygi SP, Kaelin WG, Zhang Q
JournalGenes Dev
Date Published2014 Jul 01
KeywordsAnimals, Cell Line, Cells, Cultured, Cyclin D1, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Regulation, Neoplastic, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, MCF-7 Cells, Mice, Protein Binding, Protein Stability, Ubiquitin Thiolesterase

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.

Alternate JournalGenes Dev
PubMed ID24990963
PubMed Central IDPMC4083087
Grant List1F32CA139929-01 / CA / NCI NIH HHS / United States
1K99CA160351-01 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
2R01CA68490-16 / CA / NCI NIH HHS / United States
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Ji-Hye Paik, Ph.D.

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