Regulation of Histone Deacetylase 6 Activity <i>via</i> <i>S</i>-Nitrosylation

Abstract

Nitric oxide (NO) is a gaseous regulatory factor produced by NO synthases (NOS) and it plays several critical roles via S-nitrosylation of protein cysteine residues. Histone deacetylase (HDAC) functions in the maintenance/balance of chromatin acetylation and contributes to transcriptional supression. It has been reported that S-nitrosylation of HDAC2 is involved in the regulation of deacetylase activity. However, it remains unknown whether other subtypes of the HDAC family are S-nitrosylated. In the present study, we found that HDAC6 is a target of NO. A biotin-switch assay revealed that endogenous HDAC6 is S-nitrosylated by both NO donors and NO derived from the inducible type of NOS in cells treated with cytokines. NO led to suppressed deacetylase activity in vitro and increased acetylated α-tubulin, a major substrate for HDAC6, in A549 cells. These findings suggest that S-nitrosylation of HDAC6 plays a pivotal role in the regulation of protein acetylation.

Attenuation of Macrophage Migration Inhibitory Factor-Stimulated Signaling <i>via</i> <i>S</i>-Nitrosylation

“…[10][11][12] MIF acts as a ligand for the type II transmembrane receptor, the CD74/ CD44 complex, to activate the phosphatidylinositol 3-kinase (PI3K)/Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways, which induce the expressions of brainderived neurotrophic factor (BDNF). [13][14][15][16] Here, we show that MIF is S-nitrosylated by a physiological NO donor. We also determined that the induction of S-nitrosylation resulted in a loss of MIF activities, such as the stimulation of PI3K/Akt and p38 MAPK signaling pathways, and the induction of BDNF expression.…”

HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

“…Alternatively, methods to target the upstream regulators of HDAC6 could indirectly decrease its protein levels and reduce deacetylase and E3 ubiquitin ligase activity. For instance, tamoxifen treatment of MCF-7 breast cancer cells prevented estradiol-stimulated HDAC6 accumulation and α-tubulin deacetylation [ 57 ], and nitric oxide (NO) is able to increase the acetylation of α-tubulin in A549 cells by preventing the essential S-nitrosylation of HDAC6 [ 58 ]. More directly, Cullin 3SPOP has been reported to destabilize HDAC6 via polyubiquitination, and this interaction has suggested that SPOP serves a tumor suppressor function through this mechanism [ 59 ].…”

Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells

“…Interestingly, Hdac1 and Hdac2 are differentially regulated by numerous post-translational modifications (PTMs) 17 . Hdac1 has been reported phosphorylated, acetylated, SUMOylated, and ubiquitinylated, while Hdac2, similarly to Hdac6 18 , was also found S-nitrosylated. Surprisingly, in skeletal muscle, Hdac2 S-nitrosylation seemed to have negative effects on the function of both Hdacs 10 .…”