BMB Rep. 2016; 49(5): 245-246  
Regulation of HIF-1α stability by lysine methylation
Sung Hee Baek1,* & Keun Il Kim2,*
1School of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 08826, 2Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, Korea
Correspondence to: Sung Hee Baek, E-mail:, Keun Il Kim, E-mail:
Received: March 9, 2016; Published online: May 31, 2016.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

The level and activity of critical regulatory proteins in cells are tightly controlled by several tiers of post-translational modifications. HIF-1α is maintained at low levels under normoxia conditions by the collaboration between PHD proteins and the VHL-containing E3 ubiquitin ligase complex. We recently identified a new physiologically relevant mechanism that regulates HIF-1α stability in the nucleus in response to cellular oxygen levels. This mechanism is based on the collaboration between the SET7/9 methyltransferase and the LSD1 demethylase. SET7/9 adds a methyl group to HIF-1α, which triggers degradation of the protein by the ubiquitin-proteasome system, whereas LSD1 removes the methyl group, leading to stabilization of HIF-1α under hypoxia conditions. In cells from knock-in mice with a mutation preventing HIF-1α methylation (Hif1αKA/KA), HIF-1α levels were increased in both normoxic and hypoxic conditions. Hif1αKA/KA knock-in mice displayed increased hematological parameters, such as red blood cell count and hemoglobin concentration. They also displayed pathological phenotypes; retinal and tumor-associated angiogenesis as well as tumor growth were increased in Hif1αKA/KA knock-in mice. Certain human cancer cells exhibit mutations that cause defects in HIF-1α methylation. In summary, this newly identified methylation-based regulation of HIF-1α stability constitutes another layer of regulation that is independent of previously identified mechanisms.
Keywords: HIF-1α, LSD1, Lysine methylation, SET7/9, Ubiquitin

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