CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here, we generated a genome-wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild-type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation; additionally, we find its pharmacological inhibition to significantly impact tumor growth in vitro and in vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation.
CIC-DUX4重排肉瘤（CDS）是一种罕见且具有侵袭性的软组织肿瘤，好发于青壮年。该疾病的关键致癌驱动因素是由染色体重排导致的CIC-DUX4融合蛋白表达。CIC-DUX4具有染色质结合特性，因此被认为是一种异常转录因子。然而，由CIC-DUX4诱导的染色质重塑事件尚不明确，这限制了我们为这类患者寻找基于新机制的治疗策略的能力。本研究通过人类CDS细胞模型及原发肿瘤样本，绘制了CIC-DUX4在全基因组范围内的DNA占据图谱及其相关的染色质状态。结合染色质分析、邻近连接实验以及遗传学和药理学扰动手段，我们发现CIC-DUX4在其结合位点发挥强效转录激活作用。这一特性与野生型CIC蛋白的抑制功能相反，主要通过CIC-DUX4与乙酰转移酶p300的直接相互作用介导。与此一致的是，我们证明p300对CDS肿瘤细胞增殖至关重要；此外，我们发现其药理学抑制能在体外和体内显著影响肿瘤生长。综上所述，本研究阐明了CIC-DUX4介导的转录调控机制。
肿瘤(癌症)患者之家