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Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1015-1020. doi: 10.1073/pnas.1711477115. Epub 2018 Jan 16.

Kinase-independent function of E-type cyclins in liver cancer.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
2
Department of Genetics, Harvard Medical School, Boston, MA 02115.
3
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
4
Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
5
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215.
6
Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, MA 01536.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215; peter_sicinski@dfci.harvard.edu.

Abstract

E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin E might represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.

KEYWORDS:

E-type cyclins; cell cycle; cyclin-dependent kinase CDK2; liver cancer

PMID:
29339491
PMCID:
PMC5798328
DOI:
10.1073/pnas.1711477115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: P.S. is a consultant and a recipient of a research grant from Novartis.

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