ZIC1 Overexpression Is Oncogenic in Liposarcoma

Abstract

Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity, with five recognized subtypes. Currently, the mainstay of therapy for liposarcoma is surgical excision since liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of liposarcoma compared with normal fat and in liposarcoma cell lines compared with adipose-derived stem cells (ASC). Here we show that ZIC1 contributes to the pathogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either ASC or a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 protein, and the down-regulation of pro-survival target genes: BCL2L13, JunD, Fam57A, and EIF3M. Our results demonstrate that ZIC1 expression is essential for liposarcomagenesis and that targeting ZIC1 or its downstream targets may lead to novel therapy for liposarcoma.

The MYC , TERT , and ZIC1 Genes Are Common Targets of Viral Integration and Transcriptional Deregulation in Avian Leukosis Virus Subgroup J-Induced Myeloid Leukosis

“…We did not determine the protein level of the TERT protein because of the absence of a specific anti-chicken-TERT antibody. Upregulation of MYC, TERT, and ZIC1 expression has previously been observed in human cancers (30)(31)(32), suggesting that their activation is required for tumor initiation and/or progression. To survey these CIS genes in ALV-J-induced tumors, we performed qRT-PCR on ALV-J-positive ML livers and uninfected nontumor livers from a tissue collection available at our institution.…”

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

“…[40][41][42] The ZIC transcription factor family, two members of which were significantly upregulated in our synovial sarcoma samples, is normally involved in brain and neuronal development and is overexpressed in liposarcoma and meningioma relative to normal tissue. 43,44 Some of the top genes in our analysis, such as cystatin D (CST5) and ARHGAP36 in epithelioid sarcoma, have been previously reported to be dysregulated in cancer cells. 45,46 Yet, very little information has been published on the expression pattern or biologic function of others that we identified.…”

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

“…Conversely, transcription factors that promote proliferation, such as Zic1 and Zic3 (Inoue et al, 2007;Pourebrahim et al, 2007;Brill et al, 2010;Watabe et al, 2011), were upregulated in the Pax6…”

“…6G; Fig. 7A,B) (Pourebrahim et al, 2007;Brill et al, 2010;Watabe et al, 2011) and Zic3 (Inoue et al, 2007), or regulating the progression through the cell cycle, such as Id4 (Fig. 6G) (Yun et al, 2004).…”