RESUMO
Transcription factor fusions (TFFs) are present in â¼30% of soft-tissue sarcomas. TFFs are not readily "druggable" in a direct pharmacologic manner and thus have proven difficult to target in the clinic. A prime example is the CIC-DUX4 oncoprotein, which fuses Capicua (CIC) to the double homeobox 4 gene, DUX4. CIC-DUX4 sarcoma is a highly aggressive and lethal subtype of small round cell sarcoma found predominantly in adolescents and young adults. To identify new therapeutic targets in CIC-DUX4 sarcoma, we performed chromatin immunoprecipitation sequencing analysis using patient-derived CIC-DUX4 cells. We uncovered multiple CIC-DUX4 targets that negatively regulate MAPK-ERK signaling. Mechanistically, CIC-DUX4 transcriptionally up-regulates these negative regulators of MAPK to dampen ERK activity, leading to sustained CIC-DUX4 expression. Genetic and pharmacologic MAPK-ERK activation through DUSP6 inhibition leads to CIC-DUX4 degradation and apoptotic induction. Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein and provide a precision-based strategy to combat this lethal cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Sarcoma/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Fosfatase 6 de Especificidade Dupla/genética , Fosfatase 6 de Especificidade Dupla/metabolismo , Feminino , Genes Homeobox , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Sarcoma/genética , Sarcoma de Ewing/genética , Sarcoma de Células Pequenas/genética , Fatores de Transcrição/genética , Translocação Genética/genéticaRESUMO
Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers.