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

PLoS One. 2017 Aug 2;12(8):e0182291. doi: 10.1371/journal.pone.0182291. eCollection 2017.


Tricellular tight junctions (tTJs) are specialized structures that occur where the corners of three cells meet to seal adjacent intercellular space. The molecular components of tTJs include tricellulin (TRIC) and lipolysis-stimulated lipoprotein receptor (LSR) which recruits TRIC, are required for normal hearing. Although loss of TRIC causes hearing loss with degeneration of cochlear cells, the detailed mechanisms remains unclear. In the present study, by using temperature-sensitive mouse cochlear cells, US/VOT-E36 cell line, we investigated the changes of TRIC and LSR during cochlear cell differentiation and the effects of histone deacetylase (HDAC) inhibitors against cell degeneration induced by loss of TRIC and LSR. During cell differentiation induced by the temperature change, expression of TRIC and LSR were clearly induced. Treatment with metformin enhanced expression TRIC and LSR via AMPK during cell differentiation. Loss of TRIC and LSR by the siRNAs induced cell death in differentiated cells. Treatment with HDAC inhibitors trichostatin A and HDAC6 inhibitor prevented the cell death induced by loss of TRIC and LSR. Collectively, these findings suggest that both tTJ proteins TRIC and LSR have crucial roles for the differentiated cochlear cell survival, and that HDAC inhibitors may be potential therapeutic agents to prevent hearing loss.

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Differentiation / drug effects
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Hair Cells, Auditory / cytology*
  • Hair Cells, Auditory / drug effects
  • Histone Deacetylase Inhibitors / pharmacology*
  • MARVEL Domain Containing 2 Protein / metabolism*
  • Metformin / pharmacology*
  • Mice
  • Receptors, Lipoprotein / metabolism*
  • Temperature
  • Tight Junction Proteins / metabolism
  • Tight Junctions / metabolism


  • Histone Deacetylase Inhibitors
  • MARVEL Domain Containing 2 Protein
  • Marveld2 protein, mouse
  • Receptors, Lipoprotein
  • Tight Junction Proteins
  • angulin-1 protein, mouse
  • Metformin

Grant support

This study was partially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (No. 25861575 and 15K08350). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.