CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

Ramdzan, Zubaidah M.; Nepveu, Alain

doi:10.1038/nrc3805

Cited by 102 publications

(99 citation statements)

References 84 publications

(142 reference statements)

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“…The p110 CUX1 protein is a proteolytic isoform of the full-length p200 CUX1, cleaved by CathepsinL32. Recent findings demonstrate that increased expression of p110 CUX1 functions as a transcriptional activator of genes involved in tumour cell proliferation and invasiveness333435. Importantly, we demonstrate that treatment with a γ-secretase inhibitor (GSI) is highly effective in blocking PCa progression in different Pten -deficient mouse models of PCa.…”

mentioning

confidence: 74%

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

et al. 2016

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Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.

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confidence: 74%

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

et al. 2016

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“…R1 represents annexin V-negative and 7-AAD-positive dead cells; R2 represents late apoptotic cells positive for both annexin V binding and 7-AAD uptake; R3 represents early apoptotic cells positive for annexin V and negative for 7-AAD, demonstrating cytoplasmic membrane integrity; and R4 represent annexin Vand 7-AAD-negative viable cells. case of non-oncogene addiction whereby cancer cells are dependent on the heightened activity of a protein that is not itself an oncogene (55,56). The findings that CUX2 knockdown also is detrimental to some breast tumor cells suggests that higher expression of any CUX gene may be selected in cancer cells that sustain high ROS levels (76).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, CUX1 knockdown is synthetic lethal to KRAS-transformed cells (53,54). Together, these findings illustrated a case of non-oncogene addiction whereby cancer cells have become acutely dependent on the heightened expression and activity of a protein that is not itself an oncogene (55,56).…”

Section: Reactive Oxygen Species (Ros)mentioning

confidence: 94%

CUX2 Protein Functions as an Accessory Factor in the Repair of Oxidative DNA Damage

Pal

Ramdzan

Kaur

et al. 2015

Journal of Biological Chemistry

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Background: CUX2 contains three Cut repeat domains and is expressed in postmitotic neurons. Results: Cut repeats stimulate the OGG1 DNA glycosylase, and lower or higher CUX2 expression, respectively, delays or accelerates repair of oxidative DNA damage. Conclusion: CUX2 functions as an accessory factor in base excision repair. Significance: CUX2 contributes to the maintenance of genome integrity in long lived neurons.

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“…CUX1 gene encodes a homeodomain protein that has both oncogene (cell cycle progression, cell migration and repair of DNA damages) and tumor suppressor gene (TSG) (repression of PI3K-AKT pathway and base excision repair) activities [1,2,3,4,5]. Loss of heterozygosity (LOH) at 7q22.1 where CUX1 resides is common in many cancers [1].…”

Section: Introductionmentioning

confidence: 99%

“…Loss of heterozygosity (LOH) at 7q22.1 where CUX1 resides is common in many cancers [1]. Inactivating mutations of CUX1 are present in many types of cancers [6].…”

Section: Introductionmentioning

confidence: 99%

Intratumoral heterogeneity for inactivating frameshift mutation of CUX1 and SIRT1 genes in gastric and colorectal cancers

Jo¹,

Kim²,

Yoo³

et al. 2017

pjp

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*These two authors contributed equally to this work.Both CUX1 and SIRT1 are considered tumor suppressor genes (TSGs), but it is not known whether CUX1 and SIRT1 alterations are different between high microsatellite instability (MSI-H) and microsatellite stable MSI (MSS) cancers. We identified frameshift mutations of CUX1 in 4 cases of colorectal cancer (CRC) and of SIRT1 in 1 case of gastric cancer (GC) and 3 cases of CRC. All of them were found in GC or CRC with MSI-H (3.5% of MSI-H for each gene), but neither in GC nor CRC with MSS. In addition, we analyzed intratumoral heterogeneity (ITH) of the CUX1 frameshift mutation and found that two CRCs (12.5%) harbored regional ITH of the frameshift mutation. Our data indicate that there exist frameshift mutations of CUX1 and SIRT1 genes as well as ITH of CUX1 frameshift mutation in MSI-H cancers, which together might play a role in tumorigenesis of GC and CRC with MSI-H.

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CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

Cited by 102 publications

References 84 publications

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

CUX2 Protein Functions as an Accessory Factor in the Repair of Oxidative DNA Damage

Intratumoral heterogeneity for inactivating frameshift mutation of CUX1 and SIRT1 genes in gastric and colorectal cancers

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