title: HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery.
abstract: Histone deacetylase 6 (HDAC6) plays an important role in stress responses such as misfolded protein-induced aggresomes, autophagy, and stress granules. However, precisely how HDAC6 manages response during and after cellular stress remains largely unknown. This study aimed to investigate the effect of HDAC6 on various stress and post-stress recovery responses. We showed that HIF-1α protein levels were reduced in HDAC6 knockout (KO) MEFs compared to wild-type (WT) MEFs in hypoxia. Furthermore, under hypoxia, HIF-1α levels were also reduced following rescue with either a catalytically inactive or a ubiqiutin-binding mutant HDAC6. HDAC6 deacetylated and upregulated the stability of HIF-1α, leading to activation of HIF-1α function under hypoxia. Notably, both the deacetylase and ubiquitin-binding activities of HDAC6 contributed to HIF-1α stabilization, but only deacetylase activity was required for HIF-1α transcriptional activity. Suppression of HDAC6 enhanced the interaction between HIF-1α and HSP70 under hypoxic conditions. In addition to hypoxia, depletion of HDAC6 caused hypersensitivity to cell death during oxidative stress and post-stress recovery. However, HDAC6 depletion had no effect on cell death in response to heat shock or ionizing radiation. Overall, our data suggest that HDAC6 may serve as a critical stress regulator in response to different cellular stresses.
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Ryu
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Won
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.|Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, 03722, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea. soheekwon@yonsei.ac.kr.
authors.forename: So Hee
authors.identifier: 0000-0002-3753-4415
authors.initials: SH
authors.lastname: Kwon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D018053:Arsenites / Q000633:toxicity; D015687:Cell Hypoxia; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D005720:Gamma Rays; D055786:Gene Knockout Techniques; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D018384:Oxidative Stress / Q000187:drug effects; D013696:Temperature; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D018053:Arsenites; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003035:Cobalt; D006861:Hydrogen Peroxide; C559944:HDAC4 protein, rat; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C018021:cobaltous chloride; C015001:arsenite
keywords: Apoptosis; HIF-1α; Histone deacetylase 6; Hypoxia; Oxidative stress; Post-stress recovery