p16(INK4a) -Mediated Suppression of Telomerase in Normal and Malignant Human Breast Cells

Aging Cell. 2010 Oct;9(5):736-46. doi: 10.1111/j.1474-9726.2010.00599.x. Epub 2010 Jul 14.

Abstract

The cyclin-dependent kinase inhibitor p16(INK4a) (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast / cytology
  • Breast / enzymology*
  • Breast / metabolism
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / enzymology
  • Gene Silencing
  • Histones / metabolism
  • Humans
  • Methylation
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Telomerase / antagonists & inhibitors*
  • Telomerase / genetics
  • Telomerase / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • RNA, Messenger
  • TERT protein, human
  • Telomerase