Abstract
Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRASG12D-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRASG12D overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.
Highlights
Rhabdomyosarcoma (RMS) is a pediatric cancer representing more than half of all soft tissue sarcomas in children. 350 new cases arise each year in the United States, with two-thirds of those occurring in children under the age of ten [1,2,3]
An in vivo overexpression screen in zebrafish to identify modifiers of embryonal rhabdomyosarcoma To identify chromatin-modifying factors that act as modifiers of RMS, we utilized a previously characterized model of embryonal RMS (ERMS) in the zebrafish [5]
Using gene set enrichment analysis (GSEA) on human RMS microarray data sets, we found that this list of putative or known chromatin modifiers was significantly upregulated in human ERMS and ARMS (p,0.05, Figure S1B,C)
Summary
Rhabdomyosarcoma (RMS) is a pediatric cancer representing more than half of all soft tissue sarcomas in children. 350 new cases arise each year in the United States, with two-thirds of those occurring in children under the age of ten [1,2,3]. The overall survival rate when including non-metastatic cases is currently nearly 80%, as compared to only 25% in the 1970s [4]. This is likely due to advancements in molecular biology techniques that allow for improved diagnosis and imaging, leading to tailored therapies. In about 20% of cases, the disease is metastatic at presentation, and even with aggressive treatments, five-year survival rates hover around 20%, suggesting there is still much to learn about the biology of RMS [1]. The alveolar subtype (ARMS) is more likely to occur in adolescents, be metastatic, and have a poorer prognosis. ARMS is caused by a chromosomal translocation between either Pax or Pax and forkhead transcription factors [1,8,11]
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