Mechanisms of Cables 1 gene inactivation in human ovarian cancer development

Hideo Sakamoto, Anne M. Friel, Antony W. Wood, Lankai Guo, Ana Ilic, Michael V. Seiden, Daniel C. Chung, Maureen P. Lynch, Takehiro Serikawa, Elizabeth Munro, Esther Oliva, Sandra Orsulic, Sandra D. Kirley, Rosemary Foster, Lawrence R. Zukerberg, Bo R. Rueda

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Cables 1, a cyclin-dependent kinase binding protein, is primarily involved in cell cycle regulation. Loss of nuclear Cables 1 expression is observed in human colon, lung and endometrial cancers. We previously reported that loss of nuclear Cables 1 expression was also observed with high frequency in a limited sample set of human ovarian carcinomas, although the mechanisms underlying loss of nuclear Cables 1 expression remained unknown. Our present objective was to examine Cables 1 expression in ovarian cancer in greater detail, and determine the predominant mechanisms of Cables 1 loss. We assessed potential genetic and epigenetic modifications of the Cables 1 locus through analyses of mutation, polymorphisms, loss of heterozygosity and DNA methylation. We observed a marked loss of nuclear Cables 1 expression in serous and endometrioid ovarian carcinomas that correlated with decreased Cables 1 mRNA levels. Although we detected no Cables 1 mutations, there was evidence of LOH at the Cables 1 locus and epigenetic modification of the Cables 1 promoter region in a subset of ovarian carcinomas and established cancer cell lines. From a functional perspective, over-expression of Cables 1 induced apoptosis, whereas, knockdown of Cables 1 negated this effect. Together these findings suggest that multiple mechanisms underlie the loss of Cables 1 expression in ovarian cancer cells, supporting the hypothesis that Cables 1 is a tumor suppressor in human ovarian cancer.

Original languageEnglish (US)
Pages (from-to)180-188
Number of pages9
JournalCancer Biology and Therapy
Volume7
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Cell cycle
  • Gene inactivation
  • Ovarian cancer
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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