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

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.

• Authors: So Dam Lee, Wootae Kim, Joo-Won Jeong, Jong-Wan Park, Ja-Eun Kim
• Journal: Cancer letters (Cancer Lett) Vol. 373 Issue 1 Pg. 138-145 (Apr 01 2016) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 26808575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• AK-1 compound
• Antineoplastic Agents
• BNIP3 protein, human
• Benzamides
• HIF1A protein, human
• Histone Deacetylase Inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Membrane Proteins
• Proto-Oncogene Proteins
• Sulfonamides
• Von Hippel-Lindau Tumor Suppressor Protein
• Proteasome Endopeptidase Complex
• SIRT2 protein, human
• Sirtuin 2
• VHL protein, human

Topics

• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology)
• Cell Hypoxia
• Dose-Response Relationship, Drug
• Down-Regulation
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• HeLa Cells
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Neoplasms (drug therapy, enzymology, genetics, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Stability
• Proteolysis
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA Interference
• Signal Transduction (drug effects)
• Sirtuin 2 (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology)
• Time Factors
• Transcription, Genetic (drug effects)
• Transfection
• Tumor Microenvironment
• Ubiquitination
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)