Cancer esearch apeutics , Targets , and Chemical Biology R 1 Overexpression Is Oncogenic in

Downlo sarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic ity (there are five recognized subtypes). Currently, the mainstay of therapy for liposarcoma is surgical n because liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality ated with liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations g liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for nal development, is overexpressed in all five subtypes of liposarcoma compared with normal fat, and sarcoma cell lines compared with adipose-derived stem cells. Here, we show that ZIC1 contributes to thogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoin dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either adipose-derived stem r in a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased r expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, A, and EIF3M. Our results show that ZIC1 expression is essential for liposarcomagenesis and that tarFam57 geting ZIC1 or its downstream targets might lead to novel therapy for liposarcoma. Cancer Res; 70(17); 6891–901. ©2010 AACR.