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Small molecule inhibition of Ewing sarcoma cell growth via targeting the long non coding RNA HULC
Neri Mercatelli1, Diana Fortini1, Ramona Palombo1
1Laboratory of Molecular and Cellular Neurobiology, IRCCS Santa Lucia Foundation, Rome, 00143, Italy.
Abstract:
Ewing sarcomas (ES) are aggressive pediatric cancers of bone and soft tissues characterized by in frame chromosomal translocations giving rise to chimeric transcription factors, such as EWS-FLI1. An emerging strategy to block EWS-FLI1 activity is represented by the small molecule YK-4-279, which binds to EWS-FLI1 and alters its transcriptional activity. The specific effectors of the anti-oncogenic activity of YK-4-279 are still largely unknown. Herein, by performing a high-throughput screening we identify the lncRNA HULC (Highly Upregulated in Liver Cancer) as a prominent target of YK-4-279 activity in ES cells. High levels of HULC correlate with ES aggressiveness, whereas HULC depletion reduces ES cell growth. Mechanistically, we find that HULC promotes the expression of TWIST1 oncogene by sponging miR-186. Downregulation of HULC upon treatment with YK-4-279 reduces the expression of TWIST1 by unleashing miR-186 and favoring its binding to TWIST1 transcripts. Notably, high levels of miR-186 and low levels of TWIST1 correlate with better prognosis in ES patients. Our results disclose a novel oncogenic regulatory circuit mediated by HULC lncRNA that is disrupted by the small molecule YK-4-279, with promising therapeutic implications for ES treatment.
Insights
A new study reveals that the small molecule YK-4-279 targets the HULC lncRNA in Ewing sarcoma (ES). This disruption reduces cancer aggressiveness by downregulating TWIST1, offering potential new treatments for this pediatric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ewing sarcoma (ES) is an aggressive pediatric cancer driven by chimeric transcription factors like EWS-FLI1.
- The small molecule YK-4-279 is a potential therapeutic agent that targets EWS-FLI1 activity in ES.
- The precise mechanisms and targets of YK-4-279's anti-cancer effects remain largely unelucidated.
Purpose of the Study:
- To identify novel targets of the small molecule YK-4-279 in Ewing sarcoma cells.
- To elucidate the role of identified targets in ES pathogenesis and aggressiveness.
- To explore the therapeutic potential of targeting this newly discovered regulatory circuit in ES.
Main Methods:
- High-throughput screening to identify YK-4-279 targets in ES cells.
- Quantitative analysis of lncRNA HULC and oncogene TWIST1 expression.
- Investigation of the regulatory interaction between HULC, miR-186, and TWIST1.
- Correlation analysis of molecular markers with patient prognosis.
Main Results:
- The long noncoding RNA HULC (Highly Upregulated in Liver Cancer) was identified as a key target of YK-4-279 in ES cells.
- High HULC levels correlate with increased ES aggressiveness, while HULC depletion inhibits ES cell growth.
- YK-4-279 treatment downregulates HULC, leading to reduced TWIST1 expression via the release of miR-186.
- Elevated miR-186 and reduced TWIST1 levels are associated with better prognosis in ES patients.
Conclusions:
- A novel oncogenic regulatory circuit involving HULC lncRNA, miR-186, and TWIST1 in ES has been uncovered.
- The small molecule YK-4-279 effectively disrupts this circuit, presenting a promising therapeutic strategy for Ewing sarcoma.
- This research highlights HULC as a potential therapeutic target and biomarker for ES treatment and prognosis.
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