Cyclin D1 is a direct transcriptional target of GATA3 in neuroblastoma tumor cells

Abstract

Almost all neuroblastoma tumors express excess levels of Cyclin D1 (CCND1) compared to normal tissues and other tumor types. Only a small percentage of these neuroblastoma tumors have high-level amplification of the Cyclin D1 gene. The other neuroblastoma tumors have equally high Cyclin D1 expression without amplification. Silencing of Cyclin D1 expression was previously found to trigger differentiation of neuroblastoma cells. Overexpression of Cyclin D1 is therefore one of the most frequent mechanisms with a postulated function in neuroblastoma pathogenesis. The cause for the Cyclin D1 overexpression is unknown. Here we show that Cyclin D1 overexpression results from transcriptional upregulation. To identify upstream regulators, we searched in mRNA profiles of neuroblastoma tumor series for transcription factors with expression patterns correlating to Cyclin D1. GATA3 most consistently correlated to Cyclin D1 in four independent data sets. We identified a highly conserved GATA3 binding site 27 bp upstream of the Cyclin D1 transcriptional start. Chromatin immune precipitation confirmed binding of GATA3 to the Cyclin D1 promoter. Overexpression of GATA3 induced Cyclin D1 promoter activity, which decreased after site-directed mutagenesis of the GATA3 binding site in the Cyclin D1 promoter. Silencing of GATA3 resulted in reduced Cyclin D1 promoter activity and reduced Cyclin D1 mRNA and protein levels. Moreover, GATA3 silencing caused differentiation that was similar to that caused by Cyclin D1 inhibition. These finding implicate GATA3 in Cyclin D1 overexpression in neuroblastoma.

Gata3/Ruvbl2 complex regulates T helper 2 cell proliferation via repression of Cdkn2c expression

“…In luminal progenitor cells, Gata3 was shown to directly bind to the promoter and intron of Cdkn2c and repress its expression to regulate the cell cycle (19). In addition, the involvement of Gata3 in the activation of Cyclin D1 (encoded by Ccnd1) in neuroblastoma cell lines and cell cycle entry in long-term repopulating hematopoietic stem cells were reported in previous studies (21,29). Therefore, Gata3 appears to regulate the proliferation of various cell types through several distinct mechanisms.…”

“…Earlier reports demonstrated that Gata3 regulates cell cycle in luminal progenitor cells and neuroblastoma cell via control of Cdkn2c and Ccnd1 expression, respectively (19,21). Thus, we next assessed the expression of Cdkn2c and Ccnd1 in primary Th1 and Th2 cells from wild-type or Gata3-deficient mice.…”

GATA Transcription Factors and Cancer

“…85 GATA2, GATA3, GATA4, and FOG2 are expressed in human neuroblastoma, with overexpression of GATA4 correlating with less favorable subtypes and overexpression of GATA2, GATA3, and FOG2 with more favorable subtypes. 86 In neuroblastoma cell lines, GATA3 was found to positively regulate cyclin D1, which maintains cells in an undifferentiated state, 87,88 suggesting that GATA3 has oncogenic potential in neuroblastoma.…”

Loss of GATA3 in bladder cancer promotes cell migration and invasion

“…33 In addition, cyclin D1 whose levels in the majority of neuroblastomas were much higher than those in normal tissues or other types of tumors was directly upregulated by GATA3. 35 A recent study showed that, even in breast cancer in which GATA3 loss correlated with tumor progression, GATA3 silencing resulted in inhibition of cell proliferation and facilitation of G 1 -to S-phase transition through transcriptional regulation of cyclin D1. 36 Together with the data in the current study and other findings in breast cancer, the functions of GATA3 and its downstream targets are likely cancer type-specific or possibly cell line-specific.…”