Xiao Cheng-Kun, Ren Yuexiang, Chen Qianxin, Yang Yuanzhong, Tang Luying, Xu Lin, Ren Zefang
School of Public Health, Sun Yat-sen University, Guangzhou, China.
The Sun Yat-Sen University Cancer Center, Guangzhou, China.
Epigenetics. 2024 Dec;19(1):2343593. doi: 10.1080/15592294.2024.2343593. Epub 2024 Apr 21.
Previous studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment.
以往研究表明，组蛋白甲基化在雌激素受体（ER）与乳腺癌预后的关系中起介导作用，但尚未对这种介导作用进行评估。因此，我们研究了七种组蛋白甲基化（H3K4me2、H3K4me3、H3K9me1、H3K9me2、H3K9me3、H3K27me3和H4K20me3），以确定它们是否介导ER对乳腺癌的预后影响。从1045例原发性浸润性乳腺癌构建组织芯片，并通过免疫组织化学检测组蛋白甲基化的表达。采用多因素逻辑回归分析ER与组蛋白甲基化之间的关联。运用Cox比例风险模型评估组蛋白甲基化与乳腺癌预后的关系。通过基于模型的因果中介分析评估组蛋白甲基化的中介作用。H3K9me1、H3K9me2、H3K4me2、H3K27me3、H4K20me3的高表达与ER阳性相关，而H3K9me3的高表达与ER阴性相关。较高的H3K9me2、H3K4me2和H4K20me3水平与较好的预后相关。ER与乳腺癌预后之间的关联最强由H4K20me3介导（总生存期为29.07%；无进展生存期为22.42%），其次是H3K4me2（总生存期为11.5%；无进展生存期为10.82%），最弱的是H3K9me2（总生存期为9.35%；无进展生存期为7.34%）。H4K20me3、H3K4me2和H3K9me2介导了ER与乳腺癌预后之间的关系，这将有助于从表观遗传学角度进一步阐明ER对乳腺癌预后的影响，并为乳腺癌治疗提供新思路。
