Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells
Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells
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表观遗传介导的化疗耐药卵巢癌细胞中阳性共刺激分子的免疫抑制
DOI：
10.1002/cbin.10729
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发表时间：
2017-03-01
影响因子：
3.9
通讯作者：
Cacan, Ercan
中科院分区：
文献类型：
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作者：
Cacan, Ercan
针对癌症的免疫反应是免疫激活和免疫抑制机制之间的关键平衡。卵巢癌产生一种抑制的微环境以逃避免疫消除；然而，其分子机制尚不清楚，化疗药物对肿瘤微环境是起免疫反应还是免疫抑制作用尚不清楚。4-1BB配体(4-1BBL/CD157)和OX-40配体(OX-40L/CD252)是效应细胞毒性T细胞活性的重要调节因子。与亲代化疗敏感的卵巢癌细胞相比，化疗耐药细胞中阳性共刺激分子OX-40L和4-1BBL的表达受到抑制，而免疫抑制分子程序性死亡配体-1(PD-L1/CD274)的表达增强。本研究旨在探讨化疗耐药A2780-AD卵巢癌细胞OX-40L和4-1BBL表达沉默的分子机制。OX-40L和4-1BBL的抑制是由于DNA高甲基化和组蛋白去乙酰化，这是导致癌症进展过程中基因沉默的两个重要机制。我们发现了重要的表观遗传调控因子，组蛋白脱乙酰酶1/3(HDAC1/HDAC3)和DNA甲基转移酶1(DNMT1)，它们与化疗耐药的卵巢癌细胞中的OX-40L和4-1BBL启动子异常相关。抑制HDAC1或DNMT1的表达，以及药物抑制DNMT或HDAC的酶活性，可显著增加化疗耐药细胞中OX-40L和4-1BBL的表达。本研究提示，组蛋白乙酰化缺失和DNA甲基化积聚与化疗耐药卵巢癌细胞中OX-40L和4-1BBL表达受抑制有关。这项研究是通过组蛋白去乙酰化和DNA甲基化来调节这两个分子在化疗耐药的卵巢癌细胞中的第一次报告。
The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells.