Polycomb (PcG) proteins, BMI1 and SUZ12, regulate arsenic-induced cell transformation.

Abstract

Inorganic arsenic is a well-documented human carcinogen associated with cancers of the skin, lung, liver, and bladder. However, the underlying mechanisms explaining the tumorigenic role of arsenic are not well understood. The present study explored a potential mechanism of cell transformation induced by arsenic exposure. Exposure to a low dose (0.5 μm) of arsenic trioxide (As(2)O(3)) caused transformation of BALB/c 3T3 cells. In addition, in a xenograft mouse model, tumor growth of the arsenic-induced transformed cells was dramatically increased. In arsenic-induced transformed cells, polycomb group (PcG) proteins, including BMI1 and SUZ12, were activated resulting in enhanced histone H3K27 tri-methylation levels. On the other hand, tumor suppressor p16(INK4a) and p19(ARF) mRNA and protein expression were dramatically suppressed. Introduction of small hairpin (sh) RNA-BMI1 or -SUZ12 into BALB/c 3T3 cells resulted in suppression of arsenic-induced transformation. Histone H3K27 tri-methylation returned to normal in BMI1- or SUZ12-knockdown BALB/c 3T3 cells compared with BMI1- or SUZ12-wildtype cells after arsenic exposure. As a consequence, the expression of p16(INK4a) and p19(ARF) was recovered in arsenic-treated BMI1- or SUZ12-knockdown cells. Thus, arsenic-induced cell transformation was blocked by inhibition of PcG function. Taken together, these results strongly suggest that the polycomb proteins, BMI1 and SUZ12 are required for cell transformation induced by organic arsenic exposure.

• Authors: Hong-Gyum Kim, Dong Joon Kim, Shengqing Li, Kun Yeong Lee, Xiang Li, Ann M Bode, Zigang Dong
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 38 Pg. 31920-8 (Sep 14 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22843710 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Arsenicals
• Bmi1 protein, mouse
• Cdkn2a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p16
• Histones
• Oxides
• Polycomb-Group Proteins
• Proto-Oncogene Proteins
• Suz12 protein, mouse
• Polycomb Repressive Complex 2
• Polycomb Repressive Complex 1
• Arsenic
• Arsenic Trioxide

Topics

• 3T3 Cells
• Animals
• Arsenic (chemistry)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Cell Transformation, Neoplastic
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Gene Expression Regulation, Neoplastic
• Histones (chemistry)
• Humans
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Oxides (pharmacology)
• Polycomb Repressive Complex 1 (metabolism, physiology)
• Polycomb Repressive Complex 2 (metabolism, physiology)
• Polycomb-Group Proteins (metabolism)
• Proto-Oncogene Proteins (metabolism, physiology)
• Signal Transduction