Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis

Yunho Kim; Hye Jin Nam; Junyeop Lee; Do Young Park; Chan Kim; Young Suk Yu; Dongha Kim; Se Won Park; Jinhyuk Bhin; Daehee Hwang; Ho Lee; Gou Young Koh; Sung Hee Baek

doi:10.1038/ncomms10347

Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis

Yunho Kim
, Hye Jin Nam
, Junyeop Lee
, Do Young Park
, Chan Kim
, Young Suk Yu
, Dongha Kim
, Se Won Park
, Jinhyuk Bhin
, Daehee Hwang
, Ho Lee
, Gou Young Koh
, Sung Hee Baek

Department of Anatomy

Seoul National University
Korea Advanced Institute of Science and Technology
University of Ulsan
CHA University
Institute for Basic Science
National Cancer Center Korea

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

199 Scopus citations

Abstract

Hypoxia-inducible factor-1α (HIF-1α) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1α posttranslational modifications, HIF-1α methylation and its physiological role have not yet been elucidated. Here we show that HIF-1α is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1α methylation is the modulation of HIF-1α stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1a^KA/KA allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1α stabilization. Importantly, S28Y and R30Q mutations of HIF-1α, found in human cancers, are involved in the altered HIF-1α stability. Together, these results demonstrate a role for HIF-1α methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.

Original language	English
Article number	10347
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10347
State	Published - 13 Jan 2016

Bibliographical note

Funding Information:
This work was supported by Creative Research Initiatives Program (Research Center for Chromatin Dynamics, 2009–0081563) to S.H.B., the Bio & Medical Technology Development Program (NRF-2013M3A9B6046565) to G.Y.K., Institute for Basic Science (CA1308) to D.H., Global PhD Fellowship Program (NRF-2012H1A2A1009905) to Y.S.Y. from the National Research Foundation (NRF) grant funded by the Korean government (MSIP) and a grant of the Korea Health Technology R&D Project (HI14C1976) to H.J.N. through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/ncomms10347

Cite this

@article{ad8cfb9f01f74d4cb4e498f3ec47ad63,

title = "Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis",

abstract = "Hypoxia-inducible factor-1α (HIF-1α) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1α posttranslational modifications, HIF-1α methylation and its physiological role have not yet been elucidated. Here we show that HIF-1α is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1α methylation is the modulation of HIF-1α stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1aKA/KA allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1α stabilization. Importantly, S28Y and R30Q mutations of HIF-1α, found in human cancers, are involved in the altered HIF-1α stability. Together, these results demonstrate a role for HIF-1α methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.",

author = "Yunho Kim and Nam, \{Hye Jin\} and Junyeop Lee and Park, \{Do Young\} and Chan Kim and Yu, \{Young Suk\} and Dongha Kim and Park, \{Se Won\} and Jinhyuk Bhin and Daehee Hwang and Ho Lee and Koh, \{Gou Young\} and Baek, \{Sung Hee\}",

note = "Funding Information: This work was supported by Creative Research Initiatives Program (Research Center for Chromatin Dynamics, 2009–0081563) to S.H.B., the Bio \& Medical Technology Development Program (NRF-2013M3A9B6046565) to G.Y.K., Institute for Basic Science (CA1308) to D.H., Global PhD Fellowship Program (NRF-2012H1A2A1009905) to Y.S.Y. from the National Research Foundation (NRF) grant funded by the Korean government (MSIP) and a grant of the Korea Health Technology R\&D Project (HI14C1976) to H.J.N. through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health \& Welfare.",

year = "2016",

month = jan,

day = "13",

doi = "10.1038/ncomms10347",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

TY - JOUR

T1 - Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis

AU - Kim, Yunho

AU - Nam, Hye Jin

AU - Lee, Junyeop

AU - Park, Do Young

AU - Kim, Chan

AU - Yu, Young Suk

AU - Kim, Dongha

AU - Park, Se Won

AU - Bhin, Jinhyuk

AU - Hwang, Daehee

AU - Lee, Ho

AU - Koh, Gou Young

AU - Baek, Sung Hee

N1 - Funding Information: This work was supported by Creative Research Initiatives Program (Research Center for Chromatin Dynamics, 2009–0081563) to S.H.B., the Bio & Medical Technology Development Program (NRF-2013M3A9B6046565) to G.Y.K., Institute for Basic Science (CA1308) to D.H., Global PhD Fellowship Program (NRF-2012H1A2A1009905) to Y.S.Y. from the National Research Foundation (NRF) grant funded by the Korean government (MSIP) and a grant of the Korea Health Technology R&D Project (HI14C1976) to H.J.N. through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare.

PY - 2016/1/13

Y1 - 2016/1/13

N2 - Hypoxia-inducible factor-1α (HIF-1α) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1α posttranslational modifications, HIF-1α methylation and its physiological role have not yet been elucidated. Here we show that HIF-1α is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1α methylation is the modulation of HIF-1α stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1aKA/KA allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1α stabilization. Importantly, S28Y and R30Q mutations of HIF-1α, found in human cancers, are involved in the altered HIF-1α stability. Together, these results demonstrate a role for HIF-1α methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.

AB - Hypoxia-inducible factor-1α (HIF-1α) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1α posttranslational modifications, HIF-1α methylation and its physiological role have not yet been elucidated. Here we show that HIF-1α is methylated by SET7/9 methyltransferase, and that lysine-specific demethylase 1 reverses its methylation. The functional consequence of HIF-1α methylation is the modulation of HIF-1α stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1aKA/KA allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF-1α stabilization. Importantly, S28Y and R30Q mutations of HIF-1α, found in human cancers, are involved in the altered HIF-1α stability. Together, these results demonstrate a role for HIF-1α methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer.

UR - https://www.scopus.com/pages/publications/84955123063

U2 - 10.1038/ncomms10347

DO - 10.1038/ncomms10347

M3 - Article

C2 - 26757928

AN - SCOPUS:84955123063

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10347

ER -

Methylation-dependent regulation of HIF-1α stability restricts retinal and tumour angiogenesis

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this