CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs
Ross A. Okimoto, Wei Wu, Shigeki Nanjo, Victor Olivas, Yone K. Lin, Rovingaile Kriska Ponce, Rieko Oyama, Tadashi Kondo, Trever G. Bivona
Ross A. Okimoto, Wei Wu, Shigeki Nanjo, Victor Olivas, Yone K. Lin, Rovingaile Kriska Ponce, Rieko Oyama, Tadashi Kondo, Trever G. Bivona
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Concise Communication Oncology

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

Abstract

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.

Authors

Ross A. Okimoto, Wei Wu, Shigeki Nanjo, Victor Olivas, Yone K. Lin, Rovingaile Kriska Ponce, Rieko Oyama, Tadashi Kondo, Trever G. Bivona

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Figure 4

The CCNE-CDK2 complex is a therapeutic target in CIC-DUX4 sarcoma.

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The CCNE-CDK2 complex is a therapeutic target in CIC-DUX4 sarcoma. (A) S...
(A) Subcutaneously implanted NIH 3T3 cells expressing CIC-DUX4 and treated with vehicle (n = 8) or dinaciclib (n = 8). P value, Student’s t test. Error bars represent SEM. (B) Tumor explants from mice in A. (C) Tumor weights of mice in A. P value, Student’s t test. (D) Patient-derived CIC-DUX4–expressing cells (NCC_CDS1_X1 and NCC_CDS1_X3) treated with dinaciclib or DMSO. Performed in duplicate. (E) Immunoblot of phosphorylated retinoblastoma (RB), PARP, and actin control in NCC_CDS1_X3 cells treated with dinaciclib. Representative figure; performed in duplicate. (F) Relative caspase-3/7 activity in NCC_CDS1_X1 and (G) NCC_CDS1_X3 cells treated with dinaciclib or DMSO. *P = 0.01, **P < 0.0001, 1-way ANOVA. Error bars represent SEM. (H) Subcutaneously implanted NCC_CDS1_X3 cells treated with vehicle control (n = 6) or dinaciclib (n = 7). P value, Student’s t test. Error bars reflect SEM. (I) Tumor weights from mice treated in H. P value, Student’s t test. (J) Tumor explants from mice in H. (K) Immunoblot of phosphorylated RB, total and cleaved PARP, and actin control from a NCC_CDS1_X3 tumor explant treated with vehicle (Veh) or dinaciclib. Representative figure; performed in duplicate.