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Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma
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Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma
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Journal Article
Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma
2020
Overview
Transcription factor fusions (TFFs) are present in ∼30% of softtissue 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 MAPKERK 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.
Publisher
National Academy of Sciences
Subject
/ Animals
/ Biomarkers, Tumor - genetics
/ Dual Specificity Phosphatase 6 - genetics
/ Dual Specificity Phosphatase 6 - metabolism
/ Extracellular signal-regulated kinase
/ Female
/ Gene Expression Regulation, Neoplastic - genetics
/ Homeobox
/ Humans
/ MAP Kinase Signaling System - genetics
/ MAP Kinase Signaling System - physiology
/ Mice
/ Mitogen-Activated Protein Kinases - genetics
/ Mitogen-Activated Protein Kinases - metabolism
/ Oncogene Proteins - genetics
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ Repressor Proteins - genetics
/ Sarcoma
/ Sarcoma, Small Cell - genetics
/ Transcription Factors - genetics
