2. Academic Validation
  3. AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxia

AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxia

  • Cancer Lett. 2016 Apr 1;373(1):138-145. doi: 10.1016/j.canlet.2016.01.031.
So Dam Lee 1,  Wootae Kim 2,  Joo-Won Jeong 3,  Jong-Wan Park 4,  Ja-Eun Kim 5
Affiliations

Affiliations

  • 1 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 2 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 3 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Anatomy and Neurobiology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 4 Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
  • 5 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: jekim@khu.ac.kr.
PMID: 26808575 DOI: 10.1016/j.canlet.2016.01.031
Abstract

Sirtuin family proteins are involved in the regulation of hypoxic responses which are primarily dependent on a hypoxia-inducible factor (HIF). However, few studies have examined the use of Sirtuin inhibitors to regulate HIF. The present study examined the effect of a SIRT2-specific inhibitor, AK-1, on hypoxic responses. Under hypoxic conditions, AK-1 increased the ubiquitination of HIF-1α in a VHL-dependent manner, leading to the degradation of HIF-1α via a proteasomal pathway. Downregulation of HIF-1α expression reduced its transcriptional activity and, eventually, reduced the expression of BNIP3, one of HIF-1 target genes, in AK-1-treated cells. These data demonstrate that SIRT2 inhibition attenuates hypoxic responses, and that SIRT2 inhibitors may have potential as treatments for hypoxia-associated pathological conditions.

Keywords

AK-1; Cancer; HIF-1α; Hypoxia; SIRT2.

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