Ribeiro Jennifer R, Lovasco Lindsay A, Vanderhyden Barbara C, Freiman Richard N
Pathobiology Graduate Program, Brown University , Providence, RI , USA.
Molecular and Cellular Biology and Biochemistry, Brown University , Providence, RI , USA.
Front Oncol. 2014 Mar 11;4:45. doi: 10.3389/fonc.2014.00045. eCollection 2014.
As ovarian tumors progress, they undergo a process of dedifferentiation, allowing adaptive changes in growth and morphology that promote metastasis and chemoresistance. Herein, we outline a hypothesis that TATA-box binding protein associated factors (TAFs), which compose the RNA Polymerase II initiation factor, TFIID, contribute to regulation of dedifferentiation states in ovarian cancer. Numerous studies demonstrate that TAFs regulate differentiation and proliferation states; their expression is typically high in pluripotent cells and reduced upon differentiation. Strikingly, TAF2 exhibits copy number increases or mRNA overexpression in 73% of high-grade serous ovarian cancers (HGSC). At the biochemical level, TAF2 directs TFIID to TATA-less promoters by contact with an Initiator element, which may lead to the deregulation of the transcriptional output of these tumor cells. TAF4, which is altered in 66% of HGSC, is crucial for the stability of the TFIID complex and helps drive dedifferentiation of mouse embryonic fibroblasts to induced pluripotent stem cells. Its ovary-enriched paralog, TAF4B, is altered in 26% of HGSC. Here, we show that TAF4B mRNA correlates with Cyclin D2 mRNA expression in human granulosa cell tumors. TAF4B may also contribute to regulation of tumor microenvironment due to its estrogen-responsiveness and ability to act as a cofactor for NFκB. Conversely, TAF9, a cofactor for p53 in regulating apoptosis, may act as a tumor suppressor in ovarian cancer, since it is downregulated or deleted in 98% of HGSC. We conclude that a greater understanding of mechanisms of transcriptional regulation that execute signals from oncogenic signaling cascades is needed in order to expand our understanding of the etiology and progression of ovarian cancer, and most importantly to identify novel targets for therapeutic intervention.
随着卵巢肿瘤的进展，它们会经历去分化过程，从而实现生长和形态的适应性改变，促进转移和化疗耐药性。在此，我们概述了一个假说，即构成RNA聚合酶II起始因子TFIID的TATA框结合蛋白相关因子（TAFs）有助于调节卵巢癌的去分化状态。大量研究表明，TAFs调节分化和增殖状态；它们在多能细胞中的表达通常较高，而在分化时降低。引人注目的是，在73%的高级别浆液性卵巢癌（HGSC）中，TAF2表现出拷贝数增加或mRNA过表达。在生化水平上，TAF2通过与起始子元件接触将TFIID导向无TATA框的启动子，这可能导致这些肿瘤细胞转录输出的失调。在66%的HGSC中发生改变的TAF4对于TFIID复合物的稳定性至关重要，并有助于驱动小鼠胚胎成纤维细胞向诱导多能干细胞去分化。其在卵巢中富集的旁系同源物TAF4B在26%的HGSC中发生改变。在此，我们表明TAF4B mRNA与人类颗粒细胞瘤中的细胞周期蛋白D2 mRNA表达相关。由于其雌激素反应性和作为NFκB辅因子的能力，TAF4B也可能有助于调节肿瘤微环境。相反，TAF9作为p53调节细胞凋亡的辅因子，在卵巢癌中可能起肿瘤抑制作用，因为在98%的HGSC中它被下调或缺失。我们得出结论，为了扩大我们对卵巢癌病因和进展的理解，最重要的是为治疗干预确定新靶点，需要更深入地了解执行致癌信号级联信号的转录调控机制。
