CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Jenan Al-Matouq, Thomas R. Holmes, Laura A. Hansen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1691-1700
Number of pages10
JournalMolecular Carcinogenesis
Volume58
Issue number9
DOIs
StatePublished - Jan 1 2019

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Skin Neoplasms
Cell Death
Squamous Cell Carcinoma
Skin
Apoptosis
Cell Cycle Checkpoints
Neoplasms
Phosphorylation
14-3-3 Proteins
Mutation
Cell Nucleus Active Transport
Cyclin-Dependent Kinases
Phosphoric Monoester Hydrolases
DNA Damage
Cultured Cells
Cell Cycle
Cell Proliferation
Survival
Growth
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death. / Al-Matouq, Jenan; Holmes, Thomas R.; Hansen, Laura A.

In: Molecular Carcinogenesis, Vol. 58, No. 9, 01.01.2019, p. 1691-1700.

Research output: Contribution to journalArticle

Al-Matouq, Jenan ; Holmes, Thomas R. ; Hansen, Laura A. / CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death. In: Molecular Carcinogenesis. 2019 ; Vol. 58, No. 9. pp. 1691-1700.
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