Loss of the human polycomb group protein BMI1 promotes cancer-specific cell death

L. Liu, L. G. Andrews, T. O. Tollefsbol

Research output: Contribution to journalArticlepeer-review

Abstract

The polycomb group protein BMI1 has been shown to support normal stem cell proliferation via its putative stem cell factor function, but it is not known if BMI1 may also act as a cancer stem cell factor to promote cancer development. To determine the role of human BMI1 in cancer growth and survival, we performed a loss-of-function analysis of BMI1 by RNA interference (RNAi) in both normal and malignant human cells. Our results indicate that BMI1 is crucial for the short-term survival of cancer cells but not of normal cells. We also demonstrated that loss of BMI1 was more effective in suppressing cancer cell growth than retinoid-treatment, and surviving cancer cells showed significantly reduced tumorigenicity. The cancer-specific growth retardation was mediated by an increased level of apoptosis and a delayed cell cycle progression due to the loss of BMI1. By comparison, BMI1 deficiency caused only a moderate inhibition of the cell cycle progression in normal lung cells. In both normal and cancer cells, the loss of BMI1 led to an upregulation of INK4A-ARF, but with no significant effect on the level of telomerase gene expression, suggesting that other BMI1-cooperative factors in addition to INK4A-ARF activation may be involved in the BMI1-dependent cancer-specific growth retardation. Thus, human BMI1 is critical for the short-term survival of cancer cells, and inhibition of BMI1 has minimal effect on the survival of normal cells. These findings provide a foundation for developing a cancer-specific therapy targeting BMI1.

Original languageEnglish (US)
Pages (from-to)4370-4375
Number of pages6
JournalOncogene
Volume25
Issue number31
DOIs
StatePublished - Jul 20 2006
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank Amada Cunningham, Jessica Green, Joel Berletch, Serene Lai, and Drs Mitchell Pate and Richard Jope for help with some of the cell culture work. This work was funded in part by funding from the American Institute for Cancer Research (LL, Grant # 01A015) and an Evelyn F McKnight Brain Institute Grant (TOT).

Keywords

  • BMI1
  • Cancer stem cells
  • INK4A-ARF
  • PcG proteins
  • Telomerase

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