Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss

Abstract

Loss of auditory sensory hair cells is the major pathological feature of noise-induced hearing loss (NIHL). Currently, no established clinical therapies for prevention or amelioration of NIHL are available. The absence of treatments is due to our lack of a comprehensive understanding of the molecular mechanisms underlying noise-induced damage. Our previous study indicates that epigenetic modification of histones alters hair cell survival. In this study, we investigated the effect of noise exposure on histone H3 lysine 9 acetylation (H3K9ac) in the inner ear of adult CBA/J mice and determined if inhibition of histone deacetylases by systemic administration of suberoylanilide hydroxamic acid (SAHA) could attenuate NIHL. Our results showed that H3K9ac was decreased in the nuclei of outer hair cells (OHCs) and marginal cells of the stria vascularis in the basal region after exposure to a traumatic noise paradigm known to induce permanent threshold shifts (PTS). Consistent with these results, levels of histone deacetylases 1, 2, and 3 (HDAC1, HDAC2 and HDAC3) were increased predominately in the nuclei of cochlear cells. Silencing of HDAC1, HDAC2, or HDAC3 with siRNA reduced the expression of the target HDAC in OHCs, but did not attenuate noise-induced PTS, whereas treatment with the pan-HDAC inhibitor SAHA, also named vorinostat, reduced OHC loss, and attenuated PTS. These findings suggest that histone acetylation is involved in the pathogenesis of noise-induced OHC death and hearing loss. Pharmacological targeting of histone deacetylases may afford a strategy for protection against NIHL.

Histone deacetylase inhibition prevents cell death induced by loss of tricellular tight junction proteins in temperature-sensitive mouse cochlear cells

“…iHDACs are also known to reduced noise-, gentamicin-, and cisplatin-induced ototoxicity [ 15 , 16 , 17 , 26 ]; however, the mechanism by which this occurs remains unclear. In the present study, iHDAC treatment increased both TRIC and LSR expression.…”

“…HDACs have a crucial role in both, transcription regulation and protein modification [ 30 ]. Previous studies have identified iHDACs as a promising strategy for therapeutic intervention in cancer, neurological disorders, immune disorders31, and hearing loss [ 15 , 16 , 17 , 26 ]. The deacetylation of histone core proteins may trigger cell death; thus, iHDACs could function to attenuate the apoptotic-signaling pathways involved in noise-induced hearing loss [ 15 , 16 ].…”

“…Previous studies have identified iHDACs as a promising strategy for therapeutic intervention in cancer, neurological disorders, immune disorders31, and hearing loss [ 15 , 16 , 17 , 26 ]. The deacetylation of histone core proteins may trigger cell death; thus, iHDACs could function to attenuate the apoptotic-signaling pathways involved in noise-induced hearing loss [ 15 , 16 ]. Although the precise mechanisms relating iHDACs to cochlear cell survival remain unclear, our results suggest an important role for iHDAC in increased tTJs and epithelial barrier function, thereby mitigating cochlear cell death.…”

“…Metformin is an antidiabetic drug known to protect against cisplatin-induced ototoxicity [ 13 ] and gentamycin-induced apoptosis in auditory cells [ 14 ]. Similarly, histone deacetylase inhibitors (iHDACs) reportedly limit noise-induced outer hair cells death and hearing loss [ 15 , 16 ], and attenuate gentamicin-induced hearing loss [ 17 ]. HDACs are a class of enzymes that remove acetyl groups from the lysine residues of target proteins, thereby promoting chromatin condensation and reduced transcription [ 18 ].…”

Histone Deacetylase Inhibitors Are Protective in Acute but Not in Chronic Models of Ototoxicity

“…However, in recent years, several less toxic HDAC inhibitors have been tested in clinical trials or are already approved by the FDA for the treatment of cancer. Among these, SAHA (vorinostat) attenuated hearing loss in mice caused by treatment with the combination of kanamycin (KM) and furosemide or by noise (Layman et al, 2015 ; Wen et al, 2015 ; Chen et al, 2016 ).…”