Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 32, Issue 15, Pages 3121-3131Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00204-12
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Funding
- U.S. Department of Defense (DoD) [W81XWH-07-1-0312]
- NIH [R01CA134766, R01DK060019]
- DoD [W81XWH-08-1-0432]
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Constitutive NF-kappa B activation by proinflammatory cytokines plays a major role in cancer progression. However, the underlying mechanism is still unclear. We report here that histone methyltransferase NSD2 (also known as MMSET or WHSC1), a target of bromodomain protein ANCCA/ATAD2, acts as a strong coactivator of NF-kappa B by directly interacting with NF-kappa B for activation of target genes, including those for interleukin-6 (IL-6), IL-8, vascular endothelial growth factor A (VEGFA), cyclin D, Bcl-2, and survivin, in castration-resistant prostate cancer (CRPC) cells. NSD2 is recruited to the target gene promoters upon induction and mediates NF-kappa B activation-associated elevation of histone H3K36me2 and H3K36me3 marks at the promoter, which involves its methylase activity. Interestingly, we found that NSD2 is also critical for cytokine-induced recruitment of NF-kappa B and acetyltransferase p300 and histone hyperacetylation. Importantly, NSD2 is overexpressed in prostate cancer tumors, and its overexpression correlates with NF-kappa B activation. Furthermore, NSD2 expression is strongly induced by tumor necrosis factor alpha (TNF-alpha) and IL-6 via NF-kappa B and plays a crucial role in tumor growth. These results identify NSD2 to be a key chromatin regulator of NF-kappa B and mediator of the cytokine autocrine loop for constitutive NF-kappa B activation and emphasize the important roles played by NSD2 in cancer cell proliferation and survival and tumor growth.
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