Histone methyltransferase NSD2/MMSET mediates constitutive NF-kb signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop

P. Yang, L. Guo, Z.J. Duan, C.G. Tepper, L. Xue, X. Chen, H.-J. Kung, A.C. Gao, J.X. Zou, H.-W. Chena

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91 引文 斯高帕斯(Scopus)

摘要

Constitutive NF-kB 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-kB by directly interacting with NF-kB 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-kB 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-kB and acetyltransferase p300 and histone hyperacetylation. Importantly, NSD2 is overexpressed in prostate cancer tumors, and its overexpression correlates with NF-kB activation. Furthermore, NSD2 expression is strongly induced by tumor necrosis factor alpha (TNF-α) and IL-6 via NF-kB and plays a crucial role in tumor growth. These results identify NSD2 to be a key chromatin regulator of NF-kB and mediator of the cytokine autocrine loop for constitutive NF-kB activation and emphasize the important roles played by NSD2 in cancer cell proliferation and survival and tumor growth. © 2012, American Society for Microbiology.
原文英語
頁(從 - 到)3121-3131
頁數11
期刊Molecular and Cellular Biology
32
發行號15
DOIs
出版狀態已發佈 - 8月 2012
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