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?NP63? transcriptionally activates chemokine receptor 4 (CXCR4) expression to regulate breast cancer stem cell activity and chemotaxis.

ABSTRACT: ?NP63?, the predominant TP63 isoform expressed in diverse epithelial tissues, including the mammary gland, is required for the preservation of stem cells and has been implicated in tumorigenesis and metastasis. Despite data characterizing ?NP63? as a master regulator of stem cell activity, identification of the targets underlying these effects is incompletely understood. Recently, ?NP63? was identified as a key regulator in the promotion of proinflammatory programs in squamous cell carcinoma of the head and neck. Inflammation has been implicated as a potent driver of cancer stem cell phenotypes and metastasis. In this study, we sought to identify novel targets of ?NP63? that confer cancer stem cell and prometastatic properties. Data presented here identify the gene encoding the chemokine receptor 4 (CXCR4) as a transcriptional target of ?NP63?. Our data indicate that ?NP63? enhances CXCR4 expression in breast cancer cells via its binding at two regions within the CXCR4 promoter. The CXCR4 antagonist AMD3100 was used to demonstrate that the pro-stem cell activity of ?NP63? is mediated through its regulation of CXCR4. Importantly, we show that ?NP63? promotes the chemotaxis of breast cancer cells towards the CXCR4 ligand SDF1?, a process implicated in the trafficking of breast cancer cells to sites of metastasis. This study highlights CXCR4 as a previously unidentified target of ?NP63?, which plays a significant role in mediating ?NP63?-dependent stem cell activity and chemotaxis toward SDF1?. Our findings suggest that ?NP63? regulation of CXCR4 may have strong implications in the regulation of cancer stem cells and metastasis.

SUBMITTER: DeCastro AJ

PROVIDER: S-EPMC4297234 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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ΔNP63α transcriptionally activates chemokine receptor 4 (CXCR4) expression to regulate breast cancer stem cell activity and chemotaxis.

DeCastro Andrew J AJ Cherukuri Pratima P Balboni Amanda A DiRenzo James J

Molecular cancer therapeutics 20141105 1

ΔNP63α, the predominant TP63 isoform expressed in diverse epithelial tissues, including the mammary gland, is required for the preservation of stem cells and has been implicated in tumorigenesis and metastasis. Despite data characterizing ΔNP63α as a master regulator of stem cell activity, identification of the targets underlying these effects is incompletely understood. Recently, ΔNP63α was identified as a key regulator in the promotion of proinflammatory programs in squamous cell carcinoma of ...[more]

PMID: 25376609

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Project description:BackgroundThe DNA damage response (DDR) is a mechanism that protects cells against radiation-induced oxidative DNA damage by causing cell cycle arrest and apoptosis. TP63 is a member of the tumour suppressor TP53 gene family, and ΔNp63α, a TP63 splicing variant, is constitutively expressed in the stem cell-containing basal layer of stratified epithelial tissues, including the mammary gland, where it plays a critical role in stemness and tissue development. ΔNp63α has been reported to transcriptionally inhibit the tumour suppression protein p53. This p53-repressive activity may cause genomic instability in epithelial stem cells exposed to radiation. In this study, we analysed the inhibitory effect of ΔNp63α on radiation-induced DDR.MethodsTo elucidate the role of the p53-repressive effect of ΔNp63α in radiation response, we performed a p63-siRNA knockdown experiment using human mammary epithelial cells (HMECs) expressing ΔNp63α and then performed ectopic and entopic expression experiments using human induced pluripotent stem cells (hiPSCs). After irradiation, the expression of DDR-related genes and proteins in ΔNp63α-expressing and control cells was analysed by RT-qPCR, Western blotting, and flow cytometry.ResultsThe mRNA/protein expression levels of BAX and p21 were significantly increased in p63-siRNA-treated HMECs (sip63) after X-ray irradiation (4 Gy, 0.7 Gy/min) but not in scramble-siRNA treated HMECs (scr). Transcriptomic analysis showed decreased RNA expression of cell cycle-related genes and increased expression of programmed cell death-related genes in sip63 cells compared to scr cells. Furthermore, flow cytometric analysis revealed an increase in apoptotic cells and a decrease in 5-ethynyl-2´-deoxyuridine uptake in sip63 cells compared to scr cells. On the other hand, both the ectopic and entopic expression of ΔNp63α in apoptosis-sensitive hiPSCs reduced the expression levels of BAX after irradiation and significantly decreased the number of apoptotic cells induced by radiation.ConclusionTaken together, these results indicate that ΔNp63α represses p53-related radiation-induced DDR, thereby potentially causing genomic instability in epithelial stem cells.

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?NP63? transcriptionally activates chemokine receptor 4 (CXCR4) expression to regulate breast cancer stem cell activity and chemotaxis.

Publications

ΔNP63α transcriptionally activates chemokine receptor 4 (CXCR4) expression to regulate breast cancer stem cell activity and chemotaxis.

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