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Malignant peripheral nerve sheath tumors (MPNSTs) are a type of sarcoma that generally originates from Schwann cells. The prognosis for this type of malignancy is relatively poor due to complicated genetic alterations and the lack of specific targeted therapy. Chromosome fragment 4q22‐23 is frequently deleted in MPNSTs and other human tumors, suggesting tumor suppressor genes may reside in this region. Here, we provide evidence that  SMARCAD1 , a known chromatin remodeler, is a novel tumor suppressor gene located in 4q22‐23. We identified two human homologous  smarcad1  genes ( smarcad1a  and  smarcad1b ) in zebrafish, and both genes share overlapping expression patterns during embryonic development. We demonstrated that two  smarcad1a  loss‐of‐function mutants, sa1299 and p403, can accelerate MPNST tumorigenesis in the  tp53  mutant background, suggesting  smarcad1a  is a  bona fide  tumor suppressor gene for MPNSTs. Moreover, we found that DNA double‐strand break (DSB) repair might be compromised in both mutants compared to wildtype zebrafish, as indicated by pH2AX, a DNA DSB marker. In addition, both  SMARCAD1  gene knockdown and overexpression in human cells were able to inhibit tumor growth and displayed similar DSB repair responses, suggesting proper  SMARCAD1  gene expression level or gene dosage is critical for cell growth. Given that mutations of  SMARCAD1  sensitize cells to poly ADP ribose polymerase inhibitors in yeast and the human U2OS osteosarcoma cell line, the identification of  SMARCAD1  as a novel tumor suppressor gene might contribute to the development of new cancer therapies for MPNSTs.

Loss of smarcad1a accelerates tumorigenesis of malignant peripheral nerve sheath tumors in zebrafish