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

Purpose To screen Zn2+‐dependent histone deacetylase (HDAC) 1‐11 in endometriotic cells and then evaluated the HDACs identified from the screening in ovarian endometrioma (OE) and deep endometriotic (DE) lesions, and to evaluate the therapeutic potential of HDAC8 inhibition in mice. Methods Quantification of gene and protein expression levels of HDAC1‐11 in endometriotic cells stimulated by TGF‐β1, and immunohistochemistry analysis of Class I HDACs and HDAC6 in OE/DE lesion samples. The therapeutic potential of HDAC8 inhibition was evaluated by a mouse model of deep endometriosis. Results The screening identified Class I HDACs and HDAC6 as targets of interest. Immunohistochemistry analysis found a significant elevation in HDAC8 immunostaining in both OE and DE lesions, which was corroborated by gene and protein expression quantification. For other Class I HDACs and HDAC6, their lesional expression was more subtle and nuanced. HDAC1 and HDAC6 staining was significantly elevated in DE lesions while HDAC2 and HDAC3 staining was reduced in DE lesions. Treatment of mice with induced deep endometriosis with an HDAC8 inhibitor resulted in significantly longer hotplate latency, a reduction of lesion weight by nearly two‐thirds, and significantly reduced lesional fibrosis. Conclusions These findings highlight the progression‐dependent nature of specific HDAC aberrations in endometriosis, and demonstrate, for the first titme, the therapeutic potential of suppressing HDAC8. Among 11 Zn2+‐dependent HDACs, HDAC8 was identified to be among several other HDACs that are aberrantly expressed in endometriosis, and treatment of mice with induced deep endometriosis with an HDAC8 inhibitor resulted in significantly improved pain behavior, a reduction of lesion weight, and significantly reduced lesional fibrosis.