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Tumor and Stem Cell Biology

Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility

Luisa F. Escobar-Hoyos, Ruchi Shah, Lucia Roa-Peña, Elizabeth A. Vanner, Nilofar Najafian, Anna Banach, Erik Nielsen, Ramsey Al-Khalil, Ali Akalin, David Talmage and Kenneth R. Shroyer
Luisa F. Escobar-Hoyos
1Department of Pharmacological Sciences, Stony Brook Medicine, Stony Brook, New York.
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
3Department of Biology, Research Group Genetic Toxicology and Cytogenetics, Department of Natural Sciences and Education, Universidad del Cauca, Popayán, Cauca, Colombia.
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Ruchi Shah
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
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Lucia Roa-Peña
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
4Department of Pathology, School of Medicine, National University of Colombia, Bogotá, Cundinamarca, Colombia.
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Elizabeth A. Vanner
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
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Nilofar Najafian
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
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Anna Banach
5Molecular and Cellular Biology, Stony Brook Medicine, Stony Brook, New York.
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Erik Nielsen
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
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Ramsey Al-Khalil
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
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Ali Akalin
6Department of Pathology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts.
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David Talmage
1Department of Pharmacological Sciences, Stony Brook Medicine, Stony Brook, New York.
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Kenneth R. Shroyer
2Department of Pathology, Stony Brook Medicine, Stony Brook, New York.
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  • For correspondence: kenneth.shroyer@stonybrookmedicine.edu
DOI: 10.1158/0008-5472.CAN-15-0293
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Abstract

Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27KIP1 as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27KIP1. We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27KIP1 during G1 phase of the cell cycle. p27KIP1 lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27KIP1, whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27KIP1. In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27KIP1 were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27KIP1 to influence cervical cancer pathogenesis. Cancer Res; 75(17); 1–13. ©2015 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received January 28, 2015.
  • Revision received April 29, 2015.
  • Accepted May 14, 2015.
  • ©2015 American Association for Cancer Research.
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This OnlineFirst version was published on August 18, 2015
doi: 10.1158/0008-5472.CAN-15-0293

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Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility
Luisa F. Escobar-Hoyos, Ruchi Shah, Lucia Roa-Peña, Elizabeth A. Vanner, Nilofar Najafian, Anna Banach, Erik Nielsen, Ramsey Al-Khalil, Ali Akalin, David Talmage and Kenneth R. Shroyer
Cancer Res August 18 2015 DOI: 10.1158/0008-5472.CAN-15-0293

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Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility
Luisa F. Escobar-Hoyos, Ruchi Shah, Lucia Roa-Peña, Elizabeth A. Vanner, Nilofar Najafian, Anna Banach, Erik Nielsen, Ramsey Al-Khalil, Ali Akalin, David Talmage and Kenneth R. Shroyer
Cancer Res August 18 2015 DOI: 10.1158/0008-5472.CAN-15-0293
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