Cancer Research: SNAI2-mediated repression of BIM protects rhabdomyosarcoma from ionizing radiation (Houghton, Ignatius, & Zheng Labs)

Long WangNicole R. HenschKathryn BondraPrethish SreenivasXiang R. ZhaoJiangfei ChenRodrigo Moreno CamposKunal BaxiAngelina V. VasevaBenjamin D. SunkelBerkley E. GryderSilvia PomellaBenjamin Z. StantonSiyuan ZhengEleanor Y. ChenRossella RotaJaved KhanPeter J. Houghton and Myron S. Ignatius

Abstract

Ionizing radiation (IR) and chemotherapy are 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. Modulating SNAI2 levels in RMS cells through its overexpression or knockdown altered radiosensitivity in vitro and in vivo. SNAI2 expression reliably promoted overall cell growth and inhibited mitochondrial apoptosis following exposure to IR, with either variable or minimal effects on differentiation and senescence, respectively. Importantly, SNAI2 knockdown increased expression of the proapoptotic BH3-only gene BIM, and ChIP-seq experiments established 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 signaling axis that could potentially predict clinical responses to IR treatment and be exploited to improve RMS therapy.

Read Full Text

__________________________________________________________

Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Through discovery, development, and dissemination of new scientific knowledge, Greehey CCRI strives to have a national and global impact on childhood cancer. Our mission consists of three key areas — research, clinical, and education.

Stay connected with the Greehey CCRI on FacebookTwitterLinkedIn, and Instagram.

_________________________________________________________

Article Categories: Featured news, Research Paper