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

Xingnan Zheng; Bo Zhai; Peppi Koivunen; Sandra J. Shin; Gang Lu; Jiayun Liu; Christoph Geisen; Abhishek A. Chakraborty; Javid J. Moslehi; David M. Smalley; Xin Wei; Xian Chen; Zhengming Chen; Justine M. Beres; Jing Zhang; Jen Lan Tsao; Mitchell C. Brenner; Yuqing Zhang; Cheng Fan; Ronald A. DePinho; Jihye Paik; Steven P. Gygi; William G. Kaelin; Qing Zhang

doi:10.1101/gad.242131.114

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

Xingnan Zheng, Bo Zhai, Peppi Koivunen, Sandra J. Shin, Gang Lu, Jiayun Liu, Christoph Geisen, Abhishek A. Chakraborty, Javid J. Moslehi, David M. Smalley, Xin Wei, Xian Chen, Zhengming Chen, Justine M. Beres, Jing Zhang, Jen Lan Tsao, Mitchell C. Brenner, Yuqing Zhang, Cheng Fan, Ronald A. DePinhoJihye Paik, Steven P. Gygi, William G. Kaelin, Qing Zhang

Cancer Biology

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1429-1444
Number of pages	16
Journal	Genes and Development
Volume	28
Issue number	13
DOIs	https://doi.org/10.1101/gad.242131.114
State	Published - Jul 1 2014

Keywords

Breast cancer
Cyclin D1
EglN2
FOXO3a
Prolyl hydroxylation
USP9x

ASJC Scopus subject areas

Genetics
Developmental Biology

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Zheng, X., Zhai, B., Koivunen, P., Shin, S. J., Lu, G., Liu, J., Geisen, C., Chakraborty, A. A., Moslehi, J. J., Smalley, D. M., Wei, X., Chen, X., Chen, Z., Beres, J. M., Zhang, J., Tsao, J. L., Brenner, M. C., Zhang, Y., Fan, C., ... Zhang, Q. (2014). Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes and Development, 28(13), 1429-1444. https://doi.org/10.1101/gad.242131.114

Zheng, 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, JL, Brenner, MC, Zhang, Y, Fan, C, DePinho, RA, Paik, J, Gygi, SP, Kaelin, WG & Zhang, Q 2014, 'Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase', Genes and Development, vol. 28, no. 13, pp. 1429-1444. https://doi.org/10.1101/gad.242131.114

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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.",

keywords = "Breast cancer, Cyclin D1, EglN2, FOXO3a, Prolyl hydroxylation, USP9x",

author = "Xingnan Zheng and Bo Zhai and Peppi Koivunen and Shin, {Sandra J.} and Gang Lu and Jiayun Liu and Christoph Geisen and Chakraborty, {Abhishek A.} and Moslehi, {Javid J.} and Smalley, {David M.} and Xin Wei and Xian Chen and Zhengming Chen and Beres, {Justine M.} and Jing Zhang and Tsao, {Jen Lan} and Brenner, {Mitchell C.} and Yuqing Zhang and Cheng Fan and DePinho, {Ronald A.} and Jihye Paik and Gygi, {Steven P.} and Kaelin, {William G.} and Qing Zhang",

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AU - Zheng, Xingnan

AU - Zhai, Bo

AU - Koivunen, Peppi

AU - Shin, Sandra J.

AU - Lu, Gang

AU - Liu, Jiayun

AU - Geisen, Christoph

AU - Chakraborty, Abhishek A.

AU - Moslehi, Javid J.

AU - Smalley, David M.

AU - Wei, Xin

AU - Chen, Xian

AU - Chen, Zhengming

AU - Beres, Justine M.

AU - Zhang, Jing

AU - Tsao, Jen Lan

AU - Brenner, Mitchell C.

AU - Zhang, Yuqing

AU - Fan, Cheng

AU - DePinho, Ronald A.

AU - Paik, Jihye

AU - Gygi, Steven P.

AU - Kaelin, William G.

AU - Zhang, Qing

PY - 2014/7/1

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N2 - 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.

AB - 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.

KW - Breast cancer

KW - Cyclin D1

KW - EglN2

KW - FOXO3a

KW - Prolyl hydroxylation

KW - USP9x

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

Abstract

Keywords

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