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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin E / deficiency
  • Cyclin E / genetics
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclins / deficiency
  • Cyclins / genetics
  • Cyclins / metabolism
  • Disease Progression
  • Female
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Oncogene Proteins / deficiency
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism


  • CCNE1 protein, human
  • CCNE2 protein, human
  • Ccne2 protein, mouse
  • Cyclin E
  • Cyclins
  • Oncogene Proteins
  • cyclin E1, mouse
  • Cyclin-Dependent Kinase 2