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

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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.

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

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NF-kappa B
Cell Survival
Cell Proliferation
Growth
Neoplasms
Cytokines
Interleukin-6
Prostatic Neoplasms
Cyclin D
Histone Acetyltransferases
histone methyltransferase
Castration
Interleukin-8
Histones
Vascular Endothelial Growth Factor A
Transcriptional Activation
Chromatin
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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title = "Histone methyltransferase NSD2/MMSET mediates constitutive NF-kb signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop",
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.",
author = "Ping Yang and Linlang Guo and Duan, {Zhijian J.} and Tepper, {Clifford G} and Ling Xue and Xinbin Chen and Hsing-Jien Kung and Gao, {Allen C} and Zou, {June X} and Hongwu Chen",
year = "2012",
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TY - JOUR

T1 - Histone methyltransferase NSD2/MMSET mediates constitutive NF-kb signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop

AU - Yang, Ping

AU - Guo, Linlang

AU - Duan, Zhijian J.

AU - Tepper, Clifford G

AU - Xue, Ling

AU - Chen, Xinbin

AU - Kung, Hsing-Jien

AU - Gao, Allen C

AU - Zou, June X

AU - Chen, Hongwu

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

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