Accumulation of cytoplasmic CDC25A in cutaneous squamous cell carcinoma leads to a dependency on CDC25A for cancer cell survival and tumor growth

Al‐Matouq, Jenan; Holmes, Thomas R.; Hammiller, Brianna; Tran, Nicholas M.; Holmes, Matti; Freeman, S. Caleb; Hansen, Laura A.

doi:10.1016/j.canlet.2017.09.023

Cited by 24 publications

(46 citation statements)

References 45 publications

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“…We previously showed that CDC25A inhibits apoptosis in skin cancer cells only when it is localized to the cytoplasm . To determine whether the cytoplasmic localization of CDC25C, observed both in vivo and in cultured SCC cells, was also necessary for its antiapoptotic function, CDC25C constructs with mutations in the NES or NLS were transfected into human cutaneous SCC cell line SCC12B.2 (Figure A,B).…”

Section: Resultsmentioning

confidence: 99%

“…Our observations involving CDC25A and SCC cell survival led us to investigate whether CDC25B and CDC25C reduced apoptosis as well. Surprisingly, given the little known role of these phosphatases in regulating apoptotic cell death, we found that both of them inhibited apoptosis in skin cancer cells and that this effect was regardless of subcellular localization, at least for CDC25C.…”

Section: Discussionmentioning

confidence: 95%

“…Surprisingly, given the little known role of these phosphatases in regulating apoptotic cell death, we found that both of them inhibited apoptosis in skin cancer cells and that this effect was regardless of subcellular localization, at least for CDC25C. Since 14‐3‐3 proteins are known antiapoptotic regulators, can interact with phosphorylated CDC25C at Ser216, and play a pivotal role in CDC25A‐mediated antiapoptotic activity, we hypothesized that 14‐3‐3 might similarly assist in CDC25C's antiapoptotic effect. However, although SCC cells exhibited elevated levels of phospho‐CDC25C at the 14‐3‐3 binding site Ser 216 (data not shown), CDC25C's antiapoptotic function did not rely on binding to 14‐3‐3.…”

Section: Discussionmentioning

confidence: 99%

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CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Al‐Matouq

Holmes

Hansen

2019

Molecular Carcinogenesis

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Non‐melanoma skin cancer frequently results from chronic exposure to ultraviolet (UV) irradiation. UV‐induced DNA damage activates cell cycle arrest checkpoints through degradation of the cyclin‐dependent kinase activators, the cell division cycle 25 (CDC25) phosphatases. We previously reported increased CDC25A in nonmelanoma skin cancer, but CDC25B and CDC25C had not been previously examined. Consequently, we hypothesized that increased expression of CDC25B and CDC25C increases tumor cell proliferation and skin tumor growth. We found that CDC25B and CDC25C were increased in mouse and human skin cancers. CDC25B was primarily cytoplasmic in skin and skin tumors and was significantly increased in the squamous cell carcinoma (SCC), while CDC25C was mostly nuclear in the skin, with an increased cytoplasmic signal in the premalignant and malignant tumors. Surprisingly, forced expression of CDC25B or CDC25C in cultured SCC cells did not affect proliferation, but instead suppressed apoptosis, while CDC25C silencing increased apoptosis without impacting proliferation. Targeting CDC25C to the nucleus via mutation of its nuclear export sequence, however, increased proliferation in SCC cells. Overexpression of CDC25C in the nuclear compartment did not hinder the ability of CDC25C to suppress apoptosis, neither did mutation of sites necessary for its interaction with 14‐3‐3 proteins. Analysis of apoptotic signaling pathways revealed that CDC25C increased activating phosphorylation of Akt on Ser473, increased inhibitory phosphorylation of proapoptotic BAD on Ser136, and increased the survival protein Survivin. Silencing of CDC25C significantly reduced Survivin levels. Taken together, these data suggest that increased expression of CDC25B or CDC25C are mechanisms by which skin cancers evade apoptotic cell death.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Al‐Matouq

Holmes

Hansen

2019

Molecular Carcinogenesis

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“…Thus, this mechanism can override the normal ATR response to UV‐induced DNA damage, allowing for the aberrant stabilization of CDC25A in conditions of chronic UV‐induced DNA damage. During skin tumor development, in both mouse models and clinical samples, there is increased expression of CDC25A and a distinct shift to the cytoplasm . In skin cancers, cytoplasmic CDC25A inhibits apoptosis but has no effect on proliferation .…”

Section: Cdc25 Proteins Accumulate In the Cytoplasm During Cutaneous mentioning

confidence: 99%

“…During skin tumor development, in both mouse models and clinical samples, there is increased expression of CDC25A and a distinct shift to the cytoplasm . In skin cancers, cytoplasmic CDC25A inhibits apoptosis but has no effect on proliferation . Interestingly, this antiapoptotic function of CDC25A in skin cancer is reliant upon having a functional NES and its association with 14‐3‐3 proteins .…”

Section: Cdc25 Proteins Accumulate In the Cytoplasm During Cutaneous mentioning

confidence: 99%

Aberrant localization of signaling proteins in skin cancer: Implications for treatment

Holmes

Dindu

Hansen

2019

Molecular Carcinogenesis

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Aberrant subcellular localization of signaling proteins can provide cancer cells with advantages such as resistance to apoptotic cell death, increased invasiveness and more rapid proliferation. Nuclear to cytoplasmic shifts in tumor‐promoting proteins can lead to worse patient outcomes, providing opportunities to target cancer‐specific processes. Herein, we review the significance of dysregulated protein localization with a focus on skin cancer. Altered localization of signaling proteins controlling cell cycle progression or cell death is a common feature of cancer. In some instances, aberrant subcellular localization results in an acquired prosurvival function. Taking advantage of this knowledge reveals novel targets useful in the development of cancer therapeutics.

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MicroRNA‐99a‐5p suppresses breast cancer progression and cell‐cycle pathway through downregulating CDC25A

Qin

Liu

2018

Journal Cellular Physiology

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In this study, we aimed to explore the association between miR-99a-5p and CDC25A in breast cancer and the regulatory mechanisms of miR-99a-5p on breast cancer. The expressions of messenger RNA and microRNAs in breast cancer tissues and adjacent tissues were analyzed by the Cancer Genome Atlas microarray analysis. Quantitative real-time polymerase chain reaction was conducted to find out the expression levels of miR-99a-5p and CDC25A. The expression levels of proteins (CDC25A, ki67, cyclin D1, p21, BAX, BCL-2, BCL-XL, MMP2, and MMP9) were determined by Western blot analysis. The relationship between miR-99a-5p and CDC25A was predicted and verified by bioinformatics analysis and dual luciferase assay. After transfection, cell proliferation, invasion, and apoptosis of breast cancer tissues were, respectively, observed by cell counting kit-8 assay, transwell assay, and flow cytometry (FCM). Furthermore, the relationship among miR-99a-5p, CDC25A, and cell-cycle progression was determined by FCM assay. The nude mouse transplantation tumor experiment was performed to verify the influence of miR-99a-5p on breast cancer cell in vivo. The expression of miR-99a-5p in breast cancer tissues and cells was significantly downregulated, whereas CDC25A expression was upregulated. MiR-99a-5p targeted CDC25A and suppressed its expression in breast cancer cells. Overexpression of miR-99a-5p and decreased expression of CDC25A could suppress breast cancer cell proliferation and invasion and facilitate apoptosis. Cell-cycle progression was significantly activated by downregulated miR-99a-5p and upregulated CDC25A. Moreover, miR-99a-5p overexpression repressed the expressions of CDC25A, marker ki67, and Cyclin D1 proteins, whereas it upregulated the expression of p21 protein. MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. K E Y W O R D S breast cancer, CDC25A, cell-cycle pathway, miR-99a-5p

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Accumulation of cytoplasmic CDC25A in cutaneous squamous cell carcinoma leads to a dependency on CDC25A for cancer cell survival and tumor growth

Cited by 24 publications

References 45 publications

CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Aberrant localization of signaling proteins in skin cancer: Implications for treatment

MicroRNA‐99a‐5p suppresses breast cancer progression and cell‐cycle pathway through downregulating CDC25A

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