Zheng Hanxi, Liu Xishi, Guo Sun-Wei
Department of Gynecology, Shanghai Obstetrics and Gynecology Hospital Fudan University Shanghai China.
Present address: Center for Human Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School Nanjing Medical University Suzhou China.
Reprod Med Biol. 2023 Aug 8;22(1):e12531. doi: 10.1002/rmb2.12531. eCollection 2023 Jan-Dec.
To screen Zn-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.
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.
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.
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.
筛选子宫内膜异位症细胞中锌依赖性组蛋白去乙酰化酶（HDAC）1 - 11，然后评估从筛选中鉴定出的HDAC在卵巢子宫内膜异位囊肿（OE）和深部子宫内膜异位（DE）病变中的情况，并评估HDAC8抑制在小鼠中的治疗潜力。
对转化生长因子-β1刺激的子宫内膜异位症细胞中HDAC1 - 11的基因和蛋白表达水平进行定量分析，并对OE/DE病变样本中的I类HDAC和HDAC6进行免疫组化分析。通过深部子宫内膜异位症小鼠模型评估HDAC8抑制的治疗潜力。
筛选确定I类HDAC和HDAC6为感兴趣的靶点。免疫组化分析发现，OE和DE病变中HDAC8免疫染色均显著升高，基因和蛋白表达定量分析也证实了这一点。对于其他I类HDAC和HDAC6，它们在病变中的表达更为微妙和细微差别。DE病变中HDAC1和HDAC6染色显著升高，而HDAC2和HDAC3染色降低。用HDAC8抑制剂治疗诱导深部子宫内膜异位症的小鼠，导致热板潜伏期显著延长，病变重量减少近三分之二，病变纤维化显著减轻。
这些发现突出了子宫内膜异位症中特定HDAC异常的进展依赖性本质，并首次证明了抑制HDAC8的治疗潜力。
