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.
Highlights
Chronic and low-dose arsenic exposure causes cancer in humans through an as yet unknown mechanism
These results strongly suggest that the polycomb proteins, BMI1 and suppressor of zeste 12 (SUZ12) are required for cell transformation induced by organic arsenic exposure
We found that exposure of BALB/c 3T3 cells to arsenic significantly increased anchorage-independent growth in a dose- and time-dependent manner (Fig. 1A)
Summary
Chronic and low-dose arsenic exposure causes cancer in humans through an as yet unknown mechanism. Results: PcG proteins, Bmi and Suz, are required for arsenic-induced cell transformation through their inhibition of tumor suppressors. In arsenic-induced transformed cells, polycomb group (PcG) proteins, including BMI1 and SUZ12, were activated resulting in enhanced histone H3K27 tri-methylation levels. 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. Our results provide a mechanism showing that PcG proteins, including BMI1 and SUZ12, are required for the cell transformation caused by lowdose arsenic exposure through the repression of tumor suppressor expression.
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