Department of Medicine.
Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.
J Clin Invest. 2019 Jul 22;129(8):3401-3406. doi: 10.1172/JCI126366.
Transcription factor fusion genes create oncoproteins that drive oncogenesis and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. Capicua-double homeobox 4 (CIC-DUX4) is a transcription factor fusion oncoprotein that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We demonstrated that increased expression of ETS variant 4 (ETV4) and cyclin E1 (CCNE1) occurs via neomorphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We uncovered a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4-expressing tumors sensitive to inhibition of the CCNE-CDK2 complex, suggesting a therapeutic strategy for CIC-DUX4-expressing tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically aberrant transcriptional regulator, with therapeutic implications.
转录因子融合基因可产生致癌蛋白，驱动肿瘤发生，是极具挑战性的治疗靶点。了解此类融合致癌蛋白促进恶变的分子靶点，为制定合理的治疗策略以改善临床预后提供了一种方法。Capicua 双同源盒 4（CIC-DUX4）是一种转录因子融合致癌蛋白，它定义了某些具有高转移倾向和不良临床结局的未分化圆形细胞肉瘤。CIC-DUX4 致癌蛋白促进这种侵袭性恶性肿瘤的分子靶点在很大程度上仍不清楚。我们证实，ETS 变体 4（ETV4）和细胞周期蛋白 E1（CCNE1）的表达增加是通过 CIC-DUX4 的新形式、直接作用发生的，分别驱动肿瘤转移和存活。我们揭示了对 CCNE-CDK2 细胞周期复合物的分子依赖性，使表达 CIC-DUX4 的肿瘤对 CCNE-CDK2 复合物的抑制敏感，这提示了针对表达 CIC-DUX4 的肿瘤的治疗策略。我们的研究结果强调了由遗传异常转录调节剂控制的转录组功能多样化的范例，具有治疗意义。
