CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs.

Autor: Okimoto RA; Department of Medicine.; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA., Wu W; Department of Medicine., Nanjo S; Department of Medicine., Olivas V; Department of Medicine., Lin YK; Department of Medicine., Ponce RK; Department of Medicine., Oyama R; Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan., Kondo T; Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan., Bivona TG; Department of Medicine.; Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA.; Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2019 Jul 22; Vol. 129 (8), pp. 3401-3406. Date of Electronic Publication: 2019 Jul 22 (Print Publication: 2019).
DOI: 10.1172/JCI126366
Abstrakt: 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.
Databáze: MEDLINE
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