CUX1 transcription factors: From biochemical activities and cell-based assays to mouse models and human diseases

Hulea, Laura; Nepveu, Alain

doi:10.1016/j.gene.2012.01.039

Cited by 66 publications

(57 citation statements)

References 93 publications

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“…CUX1 is a transcription factor that activates or represses transcription to regulate tumour progression in many cancers 26, 27. The study of anti‐angiogenesis often focuses on the regulation of angiogenesis‐pathway gene.…”

Section: Discussionmentioning

confidence: 99%

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway

Chen

Zhou

Yao

et al. 2018

J Cellular Molecular Medi

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Tumour growth depends on a continual supply of the nutrients and oxygen, which are offered by tumour angiogenesis. Our previous study showed that dipalmitoylphosphatidic acid (DPPA), a bioactive phospholipid, inhibits the growth of triple‐negative breast cancer cells. However, its direct effect on angiogenesis remains unknown. Our work showed that DPPA significantly suppressed vascular growth in the chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. Meanwhile, tumour angiogenesis and tumour growth were inhibited by DPPA in the tumour tissues of an experimental breast cancer model, a subcutaneous xenograft mouse model and a genetically engineered spontaneous breast cancer mouse model (MMTV‐PyMT). Furthermore, DPPA directly inhibited the proliferation, migration and tube formation of vascular endothelial cells. The anti‐angiogenic effect of DPPA was regulated by the inhibition of Cut‐like homeobox1 (CUX1), which transcriptionally inhibited fibroblast growth factor 1 (FGF1), leading to the downregulation of hepatocyte growth factor (HGF). This work first demonstrates that DPPA directly inhibits angiogenesis in cancer development. Our previous work along with this study suggest that DPPA functions as an anti‐tumour therapeutic drug that inhibits angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway

Chen

Zhou

Yao

et al. 2018

J Cellular Molecular Medi

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“…The transcription factors whose expression is CUX2 regulated include 11 homeobox and homeodomain-containing proteins (Cphx, CUX1, CUX2, Hmbox1, Onecut1/HNF6, Onecut2, PBX1, Prox1, Six1, Tgif2, and Zfhx4), which regulate development, differentiation, and other cellular processes (2,45). Four of these factors (CUX1, Onecut1/HNF6, Onecut2, and Prox1) are involved in liver development (15,18,31), and binding sites for one of the factors (PBX1) are enriched at male-biased liver DNase-hypersensitive sites (25). PBX1 can serve as a cofactor of other homeodomain proteins (22,38), while Tgif2 interacts with histone deacetylase I to repress gene expression (32).…”

Section: Discussionmentioning

confidence: 99%

“…CUX2 expression is ablated in adult female rat liver by hypophysectomy and can be induced in male liver to a normal female-like level by continuous GH infusion (23). CUX2 contains three Cut repeats and one homeodomain and displays a DNA binding specificity similar to that of the related protein CUX1 (15), but it exhibits more rapid DNA binding kinetics (10). Similar to CUX1, CUX2 can repress the p21 WAF1/CIP1/SDI1 promoter, but unlike CUX1, CUX2 does not activate the DNA polymerase ␣ promoter (10).…”

mentioning

confidence: 99%

Impact of CUX2 on the Female Mouse Liver Transcriptome: Activation of Female-Biased Genes and Repression of Male-Biased Genes

Conforto

Zhang

Sherman

et al. 2012

Molecular and Cellular Biology

122

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The growth hormone-regulated transcription factors STAT5 and BCL6 coordinately regulate sex differences in mouse liver, primarily through effects in male liver, where male-biased genes are upregulated and many female-biased genes are actively repressed. Here we investigated whether CUX2, a highly female-specific liver transcription factor, contributes to an analogous regulatory network in female liver. Adenoviral overexpression of CUX2 in male liver induced 36% of female-biased genes and repressed 35% of male-biased genes. In female liver, CUX2 small interfering RNA (siRNA) preferentially induced genes repressed by adenovirus expressing CUX2 (adeno-CUX2) in male liver, and it preferentially repressed genes induced by adeno-CUX2 in male liver. CUX2 binding in female liver chromatin was enriched at sites of male-biased DNase hypersensitivity and at genomic regions showing male-enriched STAT5 binding. CUX2 binding was also enriched near genes repressed by adeno-CUX2 in male liver or induced by CUX2 siRNA in female liver but not at genes induced by adeno-CUX2, indicating that CUX2 binding is preferentially associated with gene repression. Nevertheless, direct CUX2 binding was seen at several highly female-specific genes that were positively regulated by CUX2, including A1bg, Cyp2b9, Cyp3a44, Tox, and Trim24. CUX2 expression and chromatin binding were high in immature male liver, where repression of adult male-biased genes and expression of adult femalebiased genes are common, suggesting that the downregulation of CUX2 in male liver at puberty contributes to the developmental changes establishing adult patterns of sex-specific gene expression. S ex differences in liver gene expression are widespread and affect a broad range of physiological processes, including steroid and drug metabolism, pheromone binding, and lipid metabolism. Hepatic sex-biased genes are regulated by growth hormone (GH) (35, 49), which is secreted by the pituitary gland in a sex-specific manner in rats, mice, and humans (16,28,44,53). Pituitary GH secretion is highly pulsatile in adult male rats and mice, where strong plasma peaks of GH are followed by periods when GH levels are below detection, whereas GH secretion is more frequent in females, resulting in a more continuous exposure to circulating GH. These sexually dimorphic plasma GH patterns stimulate sex differential patterns of tyrosine phosphorylation/activation and nuclear translocation of the transcription factors STAT5a and STAT5b (collectively, STAT5) (50). Thus, STAT5 activation is persistent in female liver but is intermittent in male liver, where it coincides with the onset of each plasma GH pulse (4, 43, 54). STAT5 positively regulates ϳ90% of male-biased genes and negatively regulates ϳ60% of female-biased genes in male mouse liver (5). STAT5 binding sites are found near 35 to 40% of sex-specific genes, suggesting they are directly regulated by STAT5 (54). However, a majority of sex-specific genes do not respond rapidly to GH-activated STAT5, suggesting indirect regulatory mechani...

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“…Many transcriptional targets and cellular functions of CUX1 readily suggest mechanisms by which increased p110 or p75 CUX1 expression might promote tumour development and progression, including acceleration of S phase entry 21,22,41,62,63 , stimulation of cell migration and invasion 13,42,[64][65][66] , resistance to apoptosis 14 , and promotion of bipolar mitosis in the presence of supernumerary centrosomes 19 (reviewed in REF. 67). In addition, a role in the tumour microenvironment has recently been described.…”

Section: Mechanisms Of Action In Cancermentioning

confidence: 99%

“…In addition, p200 CUX1 promotes genome stability through its role in base excision repair 18 . Such functions would not predict a role as an oncogene, but overexpression of either p200 or p110 CUX1 contributes to tumorigenicity in cell culture models 21,24 and in transgenic mice 16,17,19,20,61 (reviewed in REFS 28,67). Two studies showed that cancer cells are acutely dependent on the multiple roles of CUX1 in maintaining genome integrity 18,19 .…”

Section: Functions Of Cux1 That Suppress Tumour Developmentmentioning

confidence: 99%

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

2014

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CUX1 transcription factors: From biochemical activities and cell-based assays to mouse models and human diseases

Cited by 66 publications

References 93 publications

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway

Impact of CUX2 on the Female Mouse Liver Transcriptome: Activation of Female-Biased Genes and Repression of Male-Biased Genes

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

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