The role of SMARCA1 in Rhabdomyosarcoma and Skeletal Muscle Differentiation

Authors

• WJ Becker
• PB Olkhanud
• HM Maeng
• JA Berzofsky

Abstract

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue of pediatric sarcoma, and studies demonstrate that RMS arises from skeletal muscle precursor cells. RMS, genetically and histologically, is divided into two subtypes: PAX-FOXO1 fusion positive (alveolar) RMS, which is driven by chromosomal translocation involving PAX3 or PAX7 genes with FOXO1 and PAX-FOXO1 fusion negative (embryonal) RMS, which is marked by mutations in RAS isoforms and some genes such as TP53, PIK3CA, CTNNB1 and FGFR4. Chromatin was one of the earliest identified targets for cancer therapy. Several chromatin remodeling proteins are associated with cancer progression processes such as proliferation, differentiation, apoptosis, and tumorigenesis. The ISWI family protein, SMARCA1, has been implicated in tumorigenesis for several cancer types. ISWI complexes regulate cell differentiation and proliferation in other cell systems, but their impact in myogenesis is not well understood. In this study, we will characterize the function of SMARCA1 in RMS cells and skeletal muscle. We hypothesize that SMARCA1 acts to modulate chromatin accessibility, and drive RMS tumorigenic growth. Methods: We will use RNA-seq, ATAC-seq, and ChIP-seq to study the impact of SMARCA1 deletion in RMS cells. Furthermore, phenotypic experiments will be performed to determine the influence of SMARCA1 on differentiation. Results: SMARCA1 is expressed highly in RMS tissues but not in muscle tissues. In addition, we show that SMARCA1 interacts with HDAC2 in rhabdomyosarcoma cells. Conclusions: This study will deepen our understanding of how SMARCA1 impacts RMS differentiation and tumor growth and may credential SMARCA1 as a novel therapeutic target in rhabdomyosarcoma.

Scientific Focus Area: Molecular Biology and Biochemistry

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