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

Yan Geng, Wojciech Michowski, Joel M. Chick, Yaoyu E. Wang, M. Emmanuelle Jecrois, Katharine E. Sweeney, Lijun Liu, Richard C. Han, Nan Ke, Agnieszka Zagozdzon, Ewa Sicinska, Roderick T. Bronson, Steven P. Gygi, Piotr Sicinski

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish
Pages (from-to)1015-1020
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number5
DOIs
StatePublished - 30 Jan 2018
Externally publishedYes

Keywords

  • Cell cycle
  • Cyclin-dependent kinase CDK2
  • E-type cyclins
  • Liver cancer

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