Oncotarget

Research Papers:

The effect of epigenetic silencing and TP53 mutation on the expression of DLL4 in human cancer stem disorder

Zhixing Yao and Zaki A. Sherif _

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Oncotarget. 2016; 7:62976-62988. https://doi.org/10.18632/oncotarget.11316

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Abstract

Zhixing Yao1 and Zaki A. Sherif1

1 Department of Biochemistry & Molecular Biology, College of Medicine, Howard University, Washington DC, USA

Correspondence to:

Zaki A. Sherif, email:

Keywords: p53, DLL4, Notch, epigenetics, angiogenesis

Received: July 22, 2016 Accepted: August 02, 2016 Published: August 16, 2016

Abstract

The Li-Fraumeni Syndrome (LFS), a genetically rare heterogeneous cancer syndrome, is characterized primarily by a germline p53 (TP53) gene mutation. We recently discovered a balanced reciprocal chromosomal translocation t(11;15)(q23;q15) in the non-cancerous skin fibroblasts of a bilateral breast cancer patient in LFS family. This prompted us to investigate the breakpoint region of the translocation, which uncovered a gene that encodes a Notch ligand, DLL4, (locus at 15q15.1), a key target in tumor vasculature. We analyzed DLL4 gene expression and protein level in LFS non-cancerous skin fibroblast cell lines and non-LFS cancer cell lines. DLL4 is abrogated in all the LFS cells and drastically down-regulated in breast (MCF7) and brain (IMR32) cancer cells and tumor tissue samples. However, DNA methylation studies revealed that DLL4 promoter is silenced only in MCF7 but not in LFS cells. We further investigated the regulation of DLL4 gene expression by ChIP assays, which demonstrated that p53 binds to DLL4 promoter through its association with CTCF, a chromosomal networking protein CCCTC binding factor. This implies a possible karyotype-phenotype correlation with respect to DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in LFS as well as breast and brain cancer cells is significant and supports the concept that this ligand may also play a role in cancer immune-surveillance; and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. Therefore, DLL4 may provide a strong platform as an immuno-therapeutic target in LFS and cancer patients.


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