title: 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: Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors: Hong-Gyum
authors: HG
authors: Kim
authors: Dong Joon
authors: DJ
authors: Kim
authors: Shengqing
authors: S
authors: Li
authors: Kun Yeong
authors: KY
authors: Lee
authors: Xiang
authors: X
authors: Li
authors: Ann M
authors: AM
authors: Bode
authors: Zigang
authors: Z
authors: Dong
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001151:Arsenic / Q000737:chemistry*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010087:Oxides / Q000494:pharmacology; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism / Q000502:physiology*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D001152:Arsenicals; C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D010087:Oxides; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; C494163:Suz12 protein, mouse; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; D001151:Arsenic; D000077237:Arsenic Trioxide