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

Ping Yang, Linlang Guo, Zhijian J. Duan, Clifford G Tepper, Ling Xue, Xinbin Chen, Hsing-Jien Kung, Allen C Gao, June X Zou, Hongwu Chen

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3121-3131
Number of pages11
JournalMolecular and Cellular Biology
Volume32
Issue number15
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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