Corroborating evidence for aberrant expression of histone deacetylase 8 in endometriosis

Abstract

PurposeThe aim of this study was to evaluate the dynamic change in staining of Class I HDACs and Hdac6 in lesions harvested serially from different time points in mice with induced endometriosis. In addition, the effect of Hdac8 activation as well as Hdac8 and Hdac6 inhibition on lesional progression and fibrogenesis was evaluated.MethodsImmunohistochemistry analysis of Class I HDACs and Hdac6 in serially harvested lesion samples in mouse. Hdac8 activation, as well as Hdac6/8 inhibition, was evaluated in mice with induced endometriosis.ResultsWe found a progressive increase in lesional staining of Hdac1, Hdac8, and Hdac6 and gradual decrease in Hdac2 staining and consistently reduced staining of Hdac3 during the course of lesional progression. The stromal Hdac8 staining correlated most prominently with all markers of lesional fibrosis. Hdac8 activation significantly accelerated the progression and fibrogenesis of endometriotic lesions. In contrast, specific inhibition of Hdac8 or Hdac6, especially of Hdac8, significantly hindered lesional progression and fibrogenesis.ConclusionsHdac8 is progressively and aberrantly overexpressed as endometriotic lesions progress. This, along with the documented HDAC1 upregulation in endometriosis and the overwhelming evidence for the therapeutic potentials of HDACIs, calls for further and in‐depth investigation of epigenetic aberrations of endometriosis in general and of HDACs in particular.

Aberrant expression of histone deacetylase 8 in endometriosis and its potential as a therapeutic target

“…In addition, the extent of lesional fibrosis correlated positively with the lesional staining of HDAC8 and HDAC6 in both the epithelial and stromal components (r = 0.64, p = 2.7 × 10 −10 , r = 0.75, p = 2.3 × 10 −15 , r = 0.59, p = 2.0 × 10 −8 , r = 0.41, p = 2.3 × 10 −4 , respectively; Figure3E-H). Of note, these correlations were consistent with what we observed in serially harvested lesions from mice with induced endometriosis 72.…”

“…Given the results of the above ex vivo experiments and in view of the in vivo results that HDAC8 activation accelerated, while HDAC8 inhibition decelerated lesional progression and fibrogenesis, 72 we speculated that inhibition of HDAC8 may have a therapeutic effect. Consequently, we next evaluated the potential therapeutic effect of PCI‐34051 (PCI), an HDAC8‐specific inhibitor, on mice with induced deep endometriosis.…”

“…Given the results of the above ex vivo experiments and in view of the in vivo results that HDAC8 activation accelerated, while HDAC8 inhibition decelerated lesional progression and fibrogenesis, 72 we No mouse died during the experiment, and no adverse effect was detected. PCI appeared to be well tolerated in treated mice.…”

“…Of note, these correlations were consistent with what we observed in serially harvested lesions from mice with induced endometriosis. 72 …”

“…Based on the results thereof, we conducted a serial mouse experiment and evaluated the lesional staining of Class I Hdacs and Hdac6, and evaluated the effect of Hdac8 activation and suppression on lesional development—but this part is reported elsewhere. 72 We also evaluated the therapeutic effect of suppression of HDAC8 in mice with induced deep endometriosis.…”