Garcia Henry, Fleyshman Daria, Kolesnikova Katerina, Safina Alfiya, Commane Mairead, Paszkiewicz Geraldine, Omelian Angela, Morrison Carl, Gurova Kateryna
Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Oncotarget. 2011 Oct;2(10):783-96. doi: 10.18632/oncotarget.340.
The Facilitates Chromatin Transcription (FACT) chromatin remodeling complex, comprised of two subunits, SSRP1 and SPT16, is involved in transcription, replication and DNA repair. We recently showed that curaxins, small molecules with anti-cancer activity, target FACT and kill tumor cells in a FACT-dependent manner. We also found that FACT is overexpressed in human and mouse tumors and that tumor cells are sensitive to FACT downregulation. To clarify the clinical potential of FACT inhibition, we were interested in physiological role(s) of FACT in multicellular organisms. We analyzed SSRP1 and SPT16 expression in different cells, tissues and conditions using Immunohistochemical (IHC) staining of mouse and human tissues and analysis of publically available high-content gene expression datasets. Both approaches demonstrated coordinated expression of the two FACT subunits, which was primarily associated with the stage of cellular differentiation. Most cells of adult tissues do not have detectable protein level of FACT. High FACT expression was associated with stem or less-differentiated cells, while low FACT levels were seen in more differentiated cells. Experimental manipulation of cell differentiation and proliferation in vitro, as well as tissue staining for the Ki67 proliferation marker, showed that FACT expression is related more to differentiation than to proliferation. Thus, FACT may be part of a stem cell-like gene expression signature and play a role in maintaining cells in an undifferentiated state, which is consistent with its potential role as an anti-cancer target.
促进染色质转录（FACT）染色质重塑复合体由两个亚基SSRP1和SPT16组成，参与转录、复制和DNA修复。我们最近发现，具有抗癌活性的小分子curaxins靶向FACT并以FACT依赖的方式杀死肿瘤细胞。我们还发现FACT在人类和小鼠肿瘤中过表达，并且肿瘤细胞对FACT下调敏感。为了阐明抑制FACT的临床潜力，我们对FACT在多细胞生物中的生理作用感兴趣。我们使用小鼠和人类组织的免疫组织化学（IHC）染色以及公开可用的高内涵基因表达数据集分析，分析了不同细胞、组织和条件下SSRP1和SPT16的表达。两种方法均显示两个FACT亚基的协同表达，这主要与细胞分化阶段相关。成年组织的大多数细胞没有可检测到的FACT蛋白水平。高FACT表达与干细胞或分化程度较低的细胞相关，而在分化程度较高的细胞中FACT水平较低。体外对细胞分化和增殖的实验操作以及Ki67增殖标志物的组织染色表明，FACT表达与分化的关系比与增殖的关系更大。因此，FACT可能是干细胞样基因表达特征的一部分，并在维持细胞的未分化状态中发挥作用，这与其作为抗癌靶点的潜在作用一致。
