Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Abstract

Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.neural differentiation | gliomagenesis

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

“…Clinical studies have also demonstrated a correlation between poor prognosis in breast cancer patients and reduced DACH1 expression (42). Similar to what we observed for ZNF326 in TNBC cells, forced expression of DACH1 in glioma cell lines also resulted in decreased proliferation in vitro and tumor growth in vivo (39). Likewise, glioma-DACH1-low cells form spheroids in serum-free medium whereas parental glioma cells do not.…”

“…These results strongly support the hypothesis that ZNF326 is a TS gene that regulates CSC self-renewal by directly controlling the expression of genes important for CSC self-renewal. Additional support for this hypothesis has been provided by other laboratories who have shown that DACH1 inactivation increases the number of CSCs in glioma and breast cancer, whereas Gata3 negatively regulates CSCs from luminal progenitors (39)(40)(41). Clinical studies have also demonstrated a correlation between poor prognosis in breast cancer patients and reduced DACH1 expression (42).…”

DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling

“…In addition, DACH1 associates with the estrogen and androgen receptors (ER and AR) to regulate signal transduction and proliferation of breast and prostate cancer cells [17,18]. DACH1 inhibits EMT and tumor initiated cells in breast cancer and glioma [19-21]. DACH1 can directly associate with p53 and enhance its function in breast and lung cancer [10,22].…”

“…DACH1 can directly associate with p53 and enhance its function in breast and lung cancer [10,22]. Inactivation of DACH1 in human cancer tissues was observed by mechanisms of gene deletion, mutation, or promoter hypermethylation [21,23]. Clinically, a decreased expression of DACH1 in breast and endometrial cancer correlates with tumor progression, poor differentiation [23] and predicts a short survival [13,24,25].…”

t(9;13)(p12;q21) PAX5/DACH1

“…DACH1 is also frequently methylated in human colorectal cancer and methylation of DACH1 may serve as detective and prognostic marker in colorectal cancer . DACH1 regulates FGF2 (4q27)-mediated tumor-initiating activity of glioma cells and inhibits formation of tumor-initiating spheroids of glioma cells (Watanabe et al, 2011).…”