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Nicole Hensch, a graduate student in the Cell Biology, Genetics, and Molecular Medicine discipline of the Integrated Biomedical Sciences PhD program, recently published a co-first author paper in Cancer Research entitled “SNAI2-Mediated Repression of BIM Protects Rhabdomyosarcoma from Ionizing Radiation” under the guidance of Dr. Myron Ignatius.
Rhabdomyosarcoma (RMS) is the most common soft tissue pediatric malignancy in the United States, and there are currently no FDA-approved targeted therapies for these tumors. Therefore, standard of care treatments, such as surgery, chemotherapy, and radiotherapy, are usually employed. However, when tumors relapse or metastasize, the 5-year survival rate of these patients drops to less than 30%. Therefore, identifying mechanisms of relapse and resistance is vital. Their lab has established that the transcriptional repressor, SNAI2, is highly expressed in this tumor subset; however, the function of SNAI2 in RMS has not fully been elucidated. Interestingly, their lab noticed a surprising correlation between SNAI2 expression and overall sensitivity to radiation, where RMS cell lines with lower SNAI2 expression were more sensitive to radiation and vice versa. Through knockdown studies, they determined that SNAI2 was indeed responsible for this resistant-like phenotype in RMS cells and that SNAI2 knockdown cells were dying via apoptosis after exposure to radiation.
As SNAI2 is known to regulate the expression of other genes, they sought to determine which primary gene was driving apoptosis in SNAI2 knockdown cells post radiation. Although SNAI2 is known to regulate the pro-apoptotic regulator PUMA in other cancers, they surprisingly found no upregulation of PUMA in SNAI2 knockdown cells but instead saw dramatically increased expression of the pro-apoptotic regulator,BCL2L11 (BIM). Through ChIP-seq analysis, multiple SNAI2 binding peaks were observed in a downstream enhancer of BIM, a completely novel finding. Therefore, in RMS cells with high SNAI2 levels, SNAI2 can bind to the downstream enhancer and effectively inhibit the transcription of BIM, enabling cells to evade radiation-induced apoptosis. BIM was confirmed to be the primary regulator of radiation-induced apoptosis in double knockdown experiments, where RMS cells with both SNAI2 and BIM downregulated were able to escape radiation-induced apoptosis.
They are currently utilizing these results to devise a potential therapeutic regimen to sensitize RMS patient tumors to radiation, thereby delaying or preventing relapse.
This work was funded in part by the UTHSCSA Cancer Research Training Program supported by the CPRIT-funded institutional Research Training Award (RTA; RP 170345) and the Greehey Graduate Fellowship in Children’s Health.