Carcinogenesis Advance Access originally published online on March 28, 2008
Carcinogenesis 2008 29(6):1276-1281; doi:10.1093/carcin/bgn084
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Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK–MAPK pathway
Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
* To whom correspondence should be addressed. Tel: +1 845 731 3515; Fax: +1 845 351 2118; Email: costam{at}env.med.nyu.edu
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.
Abbreviations: AP, alkaline phosphatase; ERK, extracellular signal-regulated kinase; HRP, horseradish peroxidase; H3S10, histone H3 at serine 10; IE, immediate-early; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinase; Ni, nickel; NiCl2, nickel chloride; Ni3S2, nickel subsulfide; Niso4, nickel sulfate; OA, okadaic acid; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; SAPK, stress-activated protein kinase; SDS, sodium dodecyl sulfate; TBS, Tris-buffered saline
Received October 15, 2007; revised March 8, 2008; accepted March 20, 2008.
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