Journal
CARCINOGENESIS
Volume 29, Issue 6, Pages 1276-1281Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgn084
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Funding
- NCI NIH HHS [P30 CA016087-280003, P30 CA016087, CA16087] Funding Source: Medline
- NIEHS NIH HHS [P30 ES000260, P42 ES010344, R01 ES014454-02, P42 ES010344-05S2, T32-ES07324, P30 ES000260-43A1, ES005512, R01 ES014454, R01 ES005512, P42 ES010344-050002, ES014454, ES010344, ES00260, R01 ES005512-16A2] Funding Source: Medline
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Nickel (Ni) is a known carcinogen, although the mechanism of its carcinogenicity is not clear. Here, we provide evidence that Ni can induce phosphorylation of histone H3 at its serine 10 residue in a c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK)-dependent manner. Ni induces the phosphorylation of JNK, with no effect on the phosphorylation states of the extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinases. An inhibitor of JNK eliminated the Ni-initiated JNK-mediated induction of histone H3 phosphorylation at serine 10, whereas inhibitors specific for ERK or p38 kinases had no effect on the phosphorylation levels of histone H3 at serine 10 (P-H3S10) in Ni-treated cells. A complete loss of Ni ion-induced phosphorylation of H3S10 was observed when JNK was specifically knocked down with RNAi. These results are the first to show the specific JNK-mediated phosphorylation of histone H3 at its serine 10 residue. We show that addition of Ni to an in vitro P-H3S10 dephosphorylation reaction does not change the loss of phosphorylation in the reaction, supporting the notion that Ni causes H3S10 phosphorylation via the JNK/SAPK pathway. It is likely that modification of H3S10 is one of a growing number of epigenetic changes believed to be involved in the carcinogenesis caused by Ni.
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