NADH elevation during chronic hypoxia leads to VHL-mediated HIF-1α degradation via SIRT1 inhibition

Hyun Yoo Joo, Jin Kyu Jung, Mi Yeon Kim, Seon Rang Woo, Jae Min Jeong, Eun Ran Park, Yong Min Kim, Joong Jean Park, Joon Kim, Miyong Yun, Hyun Jin Shin, Kee Ho Lee

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Under conditions of hypoxia, cancer cells with hypoxia inducible factor-1α (HIF-1α) from heterogeneous tumor cells show greater aggression and progression in an effort to compensate for harsh environmental conditions. Extensive study on the stability of HIF-1α under conditions of acute hypoxia in cancer progression has been conducted, however, understanding of its involvement during the chronic phase is limited. Methods: In this study, we investigated the effect of SIRT1 on HIF1 stability in a typical chronic hypoxic conditon that maintains cells for 24 h under hypoxia using Western blotting, co-IP, measurement of intracellular NAD + and NADH levels, semi-quantitative RT-PCR analysis, invasion assay, gene knockdown. Results: Here we demonstrated that the high concentration of pyruvate in the medium, which can be easily overlooked, has an effect on the stability of HIF-1α. We also demonstrated that NADH functions as a signal for conveyance of HIF-1α degradation via the SIRT1 and VHL signaling pathway under conditions of chronic hypoxia, which in turn leads to attenuation of hypoxically strengthened invasion and angiogenic activities. A steep increase in the level of NADH occurs during chronic hypoxia, leading to upregulation of acetylation and degradation of HIF-1α via inactivation of SIRT1. Of particular interest, p300-mediated acetylation at lysine 709 of HIF-1α is recogonized by VHL, which leads to degradation of HIF-1α via ubiquitin/proteasome machinary under conditions of chronic hypoxia. In addition, we demonstrated that NADH-elevation-induced acetylation and subsequent degradation of HIF-1α was independent of proline hydroxylation. Conclusions: Our findings suggest a critical role of SIRT1 as a metabolic sensor in coordination of hypoxic status via regulation of HIF-1α stability. These results also demonstrate the involvement of VHL in degradation of HIF-1α through recognition of PHD-mediated hydroxylation in normoxia and p300-mediated HIF-1α acetylation in hypoxia.

Original languageEnglish
Article number182
JournalCell and Bioscience
Volume13
Issue number1
DOIs
Publication statusPublished - 2023 Dec

Bibliographical note

Publisher Copyright:
© 2023, Society of Chinese Bioscientists in America (SCBA).

Keywords

  • Angiogenesis
  • Chronic hypoxia
  • HIF-1α degradation
  • Invasion
  • NADH elevation
  • SIRT1
  • VHL

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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