PDF(Pubmed)
Abstract：
It is still challenging to predict the efficacy of cisplatin-based therapy, particularly in relation to the activation of macroautophagy/autophagy in oral squamous cell carcinoma (OSCC). We studied the effect of selected chromatin remodeling genes on the cisplatin resistance and their interplay with autophagy in 3-dimensional tumor model and xenografts. We analyzed gene expression patterns in the cisplatin-sensitive UMSCC1, and a paired cisplatin-resistant UM-Cis cells. Many histone protein gene clusters involved in nucleosome assembly showed significant difference of expression. Gain- and loss-of-function analyses revealed an inverse correlation between cisplatin resistance and HIST1H3D expression, while a positive correlation was observed with HIST3H2A or HIST3H2B expression. In UM-Cis, HIST3H2A- and HIST3H2B-mediated chromatin remodeling upregulates autophagy status, which results in cisplatin resistance. Additionally, knockdown of HIST3H2A or HIST3H2B downregulated autophagy-activating genes via chromatin compaction of their promoter regions. MiTF, one of the key autophagy regulators upregulated in UM-Cis, negatively regulated transcription of HIST1H3D, suggesting an interplay between chromatin remodeling-dependent cisplatin resistance and autophagy. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, protein expression pattern of the selected histone protein genes were matched with the in vitro data. By examining the relationship between autophagy and chromatin remodeling genes, we identified a set of candidate genes with potential use as markers predicting chemoresistance in OSCC biopsy samples.
摘要：
预测以顺铂为基础的治疗的疗效仍然具有挑战性。特别是与口腔鳞状细胞癌（OSCC）中巨自噬/自噬的激活有关。我们研究了在三维肿瘤模型和异种移植物中选择的染色质重塑基因对顺铂耐药性的影响及其与自噬的相互作用。我们分析了顺铂敏感的UMSCC1和配对的顺铂耐药的UM-Cis细胞中的基因表达模式。许多参与核小体组装的组蛋白基因簇表现出显著的表达差异。功能分析和功能缺失分析显示顺铂耐药与HIST1H3D表达呈负相关，而与HIST3H2A或HIST3H2B表达呈正相关。在UM-Cis中,HIST3H2A-和HIST3H2B-介导的染色质重塑上调自噬状态，导致顺铂耐药。此外,HIST3H2A或HIST3H2B的敲减通过其启动子区域的染色质压缩下调自噬激活基因。MiTF,在UM-Cis中上调的关键自噬调节因子之一，负调控转录的HIST1H3D，提示染色质重塑依赖性顺铂抵抗和自噬之间的相互作用。在比较OSCC患者顺铂敏感和不敏感组织的染色强度时，所选组蛋白基因的蛋白表达模式与体外数据相匹配。通过研究自噬与染色质重塑基因之间的关系,我们在OSCC活检样本中鉴定出一组候选基因,这些基因可能用作预测化疗耐药的标志物.
