SNAI2-mediated direct repression of BIM protects rhabdomyosarcoma from ionizing radiation
AbstractIonizing radiation (IR) and chemotherapy are the mainstays of treatment for patients with rhabdomyosarcoma (RMS). Yet, the molecular mechanisms that underlie the success or failure of radiotherapy remain unclear. The transcriptional repressor SNAI2 was previously identified as a key regulator of IR sensitivity in normal and malignant stem cells through its repression of the proapoptotic BH3-only gene PUMA. Here, we demonstrate a clear correlation between SNAI2 expression levels and radiosensitivity across multiple RMS cell lines. Moreover, modulating SNAI2 levels in RMS cells through its overexpression or knockdown can alter radiosensitivity in vitro and in vivo. SNAI2 expression reliably promotes overall cell growth and inhibits mitochondrial apoptosis following exposure to IR, with either variable or minimal effects on differentiation and senescence, respectively. Importantly, SNAI2 knockdown results in a striking increase in expression of the proapoptotic BH3-only gene BIM, and ChIP-seq experiments establish that SNAI2 is a direct repressor of BIM. Since the P53 pathway is nonfunctional in the RMS cells used in this study, we have identified a new, P53-independent SNAI2/BIM axis that could potentially predict clinical responses to IR treatment and be exploited to improve RMS therapy.HighlightsSNAI2 expression levels are directly correlated with protection from radiation in rhabdomyosarcoma.Loss of SNAI2 primes rhabdomyosarcomas for IR-induced apoptosis.SNAI2 directly represses the expression of the proapoptotic BH3-only gene BIM.