BET bromodomain inhibitors suppress EWS-FLI1-dependent transcription and the IGF1 autocrine mechanism in Ewing sarcoma.
Ewing sarcoma is driven by characteristic chromosomal translocations between the EWSR1 gene with genes encoding ETS family transcription factors (EWS-ETS), most commonly FLI1. However, direct pharmacological inhibition of transcription factors like EWS-FLI1 remains largely unsuccessful. Active gene transcription requires orchestrated actions of many epigenetic regulators, such as the bromodomain and extra-terminal domain (BET) family proteins. Emerging BET bromodomain inhibitors have exhibited promising antineoplastic activities via suppression of oncogenic transcription factors in various cancers. We reasoned that EWS-FLI1-mediated transcription activation might be susceptible to BET inhibition. In this study, we demonstrated that small molecule BET bromodomain inhibitors repressed EWS-FLI1-driven gene signatures and downregulated important target genes. However, expression of EWS-FLI1 was not significantly affected. Repression of autocrine IGF1 by BET inhibitors led to significant inhibition of the IGF1R/AKT pathway critical to Ewing sarcoma cell proliferation and survival. Consistently, BET inhibitors impaired viability and clonogenic survival of Ewing sarcoma cell lines and blocked EWS-FLI1-induced transformation of mouse NIH3T3 fibroblast cells. Selective depletion of individual BET genes partially phenocopied the actions of BET inhibitors. Finally, the prototypical BET inhibitor, JQ1, significantly repressed Ewing sarcoma xenograft tumor growth. These findings suggest therapeutic potential of BET inhibitors in Ewing sarcoma and highlight an emerging paradigm of using epigenetic agents to treat cancers driven by fusion transcription factors.
Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Sudan N
SN
Loganathan
Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Nan
N
Tang
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
Jonathan T
JT
Fleming
Department of Neurological Surgery, Vanderbilt University, Nashville, TN, USA.
Yufang
Y
Ma
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Yan
Y
Guo
Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
Scott C
SC
Borinstein
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
Chin
C
Chiang
Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.|Department of Neurological Surgery, Vanderbilt University, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Jialiang
J
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019898:Autocrine Communication / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors* / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
D000970:Antineoplastic Agents; D001381:Azepines; D007334:Insulin-Like Growth Factor I; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D051789:Proto-Oncogene Protein c-fli-1; D051057:Proto-Oncogene Proteins c-akt; D034802:RNA-Binding Protein EWS; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D014230:Triazoles; C561695:(+)-JQ1 compound; C106031:EWS-FLI fusion protein; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
BET bromodomain protein; BRD4; EWS-FLI1; Ewing sarcoma; IGF1