Researchers discover a crucial gene for the growth of Ewing’s sarcoma

Researchers from the Institute for Recerca Sant Joan de Déu (IRSJD), in collaboration with those from the Center for Genome Regulation (CRG), have found that RING1B is a critical gene in the development of Ewing’s sarcoma, a rare type of developmental cancer that occurs in bones and soft tissues. This newly discovered epigenetic susceptibility in Ewing’s sarcoma cancer cells opens the door to new therapeutic strategies.

Ewing’s sarcoma is caused by a chromosomal translocation in which the EWSR1 gene on chromosome 22 fuses with the FLI1 gene on chromosome 11. The resulting EWSR1-FLI1 fusion protein contains the transcription activation machinery of EWSR1, and the DNA-binding domain of FLI1 is the main driver of tumorigenesis.

A new study published today in Advances in science describes how the oncogenic EWSR1-FLI1 fusion protein is directed to different parts of the genome by RING1B, allowing EWSR1-FLI1 to hijack the cells’ transcription program and turn them into cancer cells.

The researchers found that RING1B and EWSR1-FLI1 are located in the same regions in the genome where RING1B is responsible for recruiting EWSR1-FLI1. EWSR1-FLI1 cannot activate its target genes and convert a cell without RING1B from a healthy to a cancerous state, as demonstrated by impaired tumor growth when RING1B is reduced.

Epigenetic inhibitors have been proposed to treat Ewing’s sarcoma and other types of cancers in children such as neuroblastoma, rhabdomyosarcoma, or synovial sarcoma. Further research could investigate the pharmacological inhibition of RING1B as a clinical therapy for the treatment of Ewing’s sarcoma.

“Our results offer impressive insights into the mechanism of Ewing’s sarcoma and help us to uncover the elusive cell of origin for this rare cancer,” says Luciano Di Croce, researcher at the Center for Genomic Regulation and one of the authors of the study. “We just have to look for high RING1B values.”

“EWSR1-FLI1 remains a challenging drug target, so understanding its addictions can offer alternative strategies for turning off its aberrant transcription program,” says Sara Sánchez-Molina, lead study author and postdoctoral fellow at the Institut de Recerca Sant Joan de Déu.

“Ewing’s tumors are paradigmatic examples of developmental cancer, where the first hit (genetic or epigenetic) occurs during embryonic development (pregnancy) and in the majority of Ewing’s sarcomas develops postnatally in certain growth stages such as puberty. The study supports the model by embryonic stem cells, characterized by high RING1B levels, able to sustain the aberrant transcription program caused by the oncogenic fusion protein. Ewing’s sarcoma occurs when the individual is born with progenitor cells that carry the fusion oncoprotein, “says Jaume Mora, Scientific Director of the Children’s Cancer Center Barcelona-Institut de Recerca Sant Joan de Déu and director of the study.

A non-coding RNA promotes pediatric bone cancer

More information:
RING1B is recruiting EWSR1-FLI1 and is cooperating in remodeling the chromatin required for Ewing’s sarcoma tumorigenesis. Advances in science (2020). DOI: 10.1126 / sciadv.aba3058

Provided by the Center for Genomic Regulation