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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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. © 2012, American Society for Microbiology.
Original languageEnglish
Pages (from-to)3121-3131
Number of pages11
JournalMolecular and Cellular Biology
Volume32
Issue number15
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

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Keywords

  • acyltransferase
  • cyclin D
  • histone methyltransferase
  • histone methyltransferase mmset
  • histone methyltransferase nsd2
  • immunoglobulin enhancer binding protein
  • interleukin 6
  • interleukin 8
  • methyltransferase
  • protein bcl 2
  • protein p300
  • survivin
  • tumor necrosis factor alpha
  • unclassified drug
  • vasculotropin A
  • acetylation
  • article
  • autocrine effect
  • cancer cell
  • castration resistant prostate cancer
  • cell proliferation
  • cell survival
  • chromatin
  • controlled study
  • enzyme activity
  • gene targeting
  • human
  • human cell
  • positive feedback
  • priority journal
  • promoter region
  • protein expression
  • protein interaction
  • tumor growth
  • Acetylation
  • Animals
  • Autocrine Communication
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Chromatin
  • Cyclin D
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Interleukin-6
  • Interleukin-8
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • NF-kappa B
  • p300-CBP Transcription Factors
  • Promoter Regions, Genetic
  • Prostatic Neoplasms
  • Proto-Oncogene Proteins c-bcl-2
  • Repressor Proteins
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Transplantation, Heterologous
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A

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