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

Research output: Contribution to journalArticle

64 Citations (Scopus)

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

Fingerprint

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

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

Cite this

Histone methyltransferase NSD2/MMSET mediates constitutive NF-kb signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. / Yang, P.; Guo, L.; Duan, Z.J.; Tepper, C.G.; Xue, L.; Chen, X.; Kung, H.-J.; Gao, A.C.; Zou, J.X.; Chena, H.-W.

In: Molecular and Cellular Biology, Vol. 32, No. 15, 08.2012, p. 3121-3131.

Research output: Contribution to journalArticle

Yang, P. ; Guo, L. ; Duan, Z.J. ; Tepper, C.G. ; Xue, L. ; Chen, X. ; Kung, H.-J. ; Gao, A.C. ; Zou, J.X. ; Chena, H.-W. / Histone methyltransferase NSD2/MMSET mediates constitutive NF-kb signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 15. pp. 3121-3131.
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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. {\circledC} 2012, American Society for Microbiology.",
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",
author = "P. Yang and L. Guo and Z.J. Duan and C.G. Tepper and L. Xue and X. Chen and H.-J. Kung and A.C. Gao and J.X. Zou and H.-W. Chena",
note = "引用次數:51 Export Date: 5 March 2018 CODEN: MCEBD 通訊地址: Zou, J.X.; UC Davis Cancer Center/Basic Sciences, University of California at Davis, Sacramento, CA, United States; 電子郵件: jxzou@ucdavis.edu 化學物質/CAS: acyltransferase, 9012-30-0, 9054-54-0; cyclin D, 146587-97-5; interleukin 8, 114308-91-7; methyltransferase, 9033-25-4; protein bcl 2, 219306-68-0; survivin, 195263-98-0; vasculotropin A, 489395-96-2; BIRC5 protein, human; Chromatin; Cyclin D; Histone-Lysine N-Methyltransferase, 2.1.1.43; Histones; Inhibitor of Apoptosis Proteins; Interleukin-6; Interleukin-8; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Repressor Proteins; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; WHSC1 protein, human, 2.1.1.43; p300-CBP Transcription Factors, 2.3.1.48; p300-CBP-associated factor, 2.3.1.48 參考文獻: Agoulnik, I.U., Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression (2005) Cancer Res, 65, pp. 7959-7967; Barish, G.D., Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response (2010) Genes Dev, 24, pp. 2760-2765; Caron, C., Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers (2010) Oncogene, 29, pp. 5171-5181; Carrozza, M.J., Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription (2005) Cell, 123, pp. 581-592; Chaturvedi, M.M., Sung, B., Yadav, V.R., Kannappan, R., Aggarwal, B.B., NF-kappaB addiction and its role in cancer: 'one size does not fit all. ' (2011) Oncogene, 30, pp. 1615-1630; Chen, C.D., Sawyers, C.L., NF- kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer (2002) Mol. Cell. Biol., 22, pp. 2862-2870; Chen, L.F., NF- kappaB RelA phosphorylation regulates RelA acetylation (2005) Mol. Cell. Biol., 25, pp. 7966-7975; Ciro, M., ATAD2 is a novel cofactor for MYC, overexpressed and amplified in aggressive tumors (2009) Cancer Res, 69, pp. 8491-8498; Dan, H.C., Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK (2008) Genes Dev, 22, pp. 1490-1500; De Santa, F., The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing (2007) Cell, 130, pp. 1083-1094; Heinz, S., Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities (2010) Mol. Cell, 38, pp. 576-589; Huang, B., Yang, X.D., Zhou, M.M., Ozato, K., Chen, L.F., Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA (2009) Mol. Cell. Biol., 29, pp. 1375-1387; Hudlebusch, H.R., The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors (2011) Clin. Cancer Res., 17, pp. 2919-2933; Jin, R.J., The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth (2008) Cancer Res, 68, pp. 6762-6769; Kalashnikova, E.V., ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2 (2010) Cancer Res, 70, pp. 9402-9412; Kim, J.Y., Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity (2008) Mol. Cell. Biol., 28, pp. 2023-2034; Kuo, A.J., NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming (2011) Mol. Cell, 44, pp. 609-620; Lamont, K.R., Tindall, D.J., Minireview: alternative activation pathways for the androgen receptor in prostate cancer (2011) Mol. Endocrinol., 25, pp. 897-907; Lauring, J., The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity (2008) Blood, 111, pp. 856-864; Lee, L.F., Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK (2004) Oncogene, 23, pp. 2197-2205; Lessard, L., Nuclear localization of nuclear factor-kappaB p65 in primary prostate tumors is highly predictive of pelvic lymph node metastases (2006) Clin. Cancer Res., 12, pp. 5741-5745; Li, Y., Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes Relevance to diabetes and inflammation (2008) J. Biol. Chem., 283, pp. 26771-26781; Li, Y., The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate (2009) J. Biol. Chem., 284, pp. 34283-34295; Louie, M.C., Androgen-induced recruitment of RNA polymerase II to a nuclear receptor-p160 coactivator complex (2003) Proc. Natl. Acad. Sci. U. S. A., 100, pp. 2226-2230; Lu, T., Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65 (2010) Proc. Natl. Acad. Sci. U. S. A., 107, pp. 46-51; Malinowska, K., Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor (2009) Endocr. Relat. Cancer, 16, pp. 155-169; Marango, J., The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor (2008) Blood, 111, pp. 3145-3154; Martinez-Garcia, E., The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells (2011) Blood, 117, pp. 211-220; Min, J., An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factorkappaB (2010) Nat. Med., 16, pp. 286-294; Nadiminty, N., Aberrant activation of the androgen receptor by NF-kappaB2/p52 in prostate cancer cells (2010) Cancer Res, 70, pp. 3309-3319; Ndlovu, M.N., Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutivetranscription across the interleukin-6 gene promoter in metastatic breast cancer cells (2009) Mol. Cell. Biol., 29, pp. 5488-5504; Nimura, K., A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome (2009) Nature, 460, pp. 287-291; Niu, Y., Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails (2010) Oncogene, 29, pp. 3593-3604; Norris, J.D., The homeodomain protein HOXB13 regulates the cellular response to androgens (2009) Mol. Cell, 36, pp. 405-416; Nowak, D.E., RelA Ser276 phosphorylation is required for activation of a subset of NF-kappaB-dependent genes by recruiting cyclindependent kinase 9/cyclin T1 complexes (2008) Mol. Cell. Biol., 28, pp. 3623-3638; Pei, H., MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites (2011) Nature, 470, pp. 124-128; Perkins, N.D., The diverse and complex roles of NF-kappaB subunits in cancer (2012) Nat. Rev. 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year = "2012",
month = "8",
doi = "10.1128/MCB.00204-12",
language = "English",
volume = "32",
pages = "3121--3131",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "15",

}

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, P.

AU - Guo, L.

AU - Duan, Z.J.

AU - Tepper, C.G.

AU - Xue, L.

AU - Chen, X.

AU - Kung, H.-J.

AU - Gao, A.C.

AU - Zou, J.X.

AU - Chena, H.-W.

N1 - 引用次數:51 Export Date: 5 March 2018 CODEN: MCEBD 通訊地址: Zou, J.X.; UC Davis Cancer Center/Basic Sciences, University of California at Davis, Sacramento, CA, United States; 電子郵件: jxzou@ucdavis.edu 化學物質/CAS: acyltransferase, 9012-30-0, 9054-54-0; cyclin D, 146587-97-5; interleukin 8, 114308-91-7; methyltransferase, 9033-25-4; protein bcl 2, 219306-68-0; survivin, 195263-98-0; vasculotropin A, 489395-96-2; BIRC5 protein, human; Chromatin; Cyclin D; Histone-Lysine N-Methyltransferase, 2.1.1.43; Histones; Inhibitor of Apoptosis Proteins; Interleukin-6; Interleukin-8; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Repressor Proteins; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; WHSC1 protein, human, 2.1.1.43; p300-CBP Transcription Factors, 2.3.1.48; p300-CBP-associated factor, 2.3.1.48 參考文獻: Agoulnik, I.U., Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression (2005) Cancer Res, 65, pp. 7959-7967; Barish, G.D., Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response (2010) Genes Dev, 24, pp. 2760-2765; Caron, C., Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers (2010) Oncogene, 29, pp. 5171-5181; Carrozza, M.J., Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription (2005) Cell, 123, pp. 581-592; Chaturvedi, M.M., Sung, B., Yadav, V.R., Kannappan, R., Aggarwal, B.B., NF-kappaB addiction and its role in cancer: 'one size does not fit all. ' (2011) Oncogene, 30, pp. 1615-1630; Chen, C.D., Sawyers, C.L., NF- kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer (2002) Mol. Cell. Biol., 22, pp. 2862-2870; Chen, L.F., NF- kappaB RelA phosphorylation regulates RelA acetylation (2005) Mol. Cell. Biol., 25, pp. 7966-7975; Ciro, M., ATAD2 is a novel cofactor for MYC, overexpressed and amplified in aggressive tumors (2009) Cancer Res, 69, pp. 8491-8498; Dan, H.C., Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK (2008) Genes Dev, 22, pp. 1490-1500; De Santa, F., The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing (2007) Cell, 130, pp. 1083-1094; Heinz, S., Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities (2010) Mol. Cell, 38, pp. 576-589; Huang, B., Yang, X.D., Zhou, M.M., Ozato, K., Chen, L.F., Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA (2009) Mol. Cell. Biol., 29, pp. 1375-1387; Hudlebusch, H.R., The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors (2011) Clin. Cancer Res., 17, pp. 2919-2933; Jin, R.J., The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth (2008) Cancer Res, 68, pp. 6762-6769; Kalashnikova, E.V., ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2 (2010) Cancer Res, 70, pp. 9402-9412; Kim, J.Y., Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity (2008) Mol. Cell. Biol., 28, pp. 2023-2034; Kuo, A.J., NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming (2011) Mol. Cell, 44, pp. 609-620; Lamont, K.R., Tindall, D.J., Minireview: alternative activation pathways for the androgen receptor in prostate cancer (2011) Mol. Endocrinol., 25, pp. 897-907; Lauring, J., The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity (2008) Blood, 111, pp. 856-864; Lee, L.F., Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK (2004) Oncogene, 23, pp. 2197-2205; Lessard, L., Nuclear localization of nuclear factor-kappaB p65 in primary prostate tumors is highly predictive of pelvic lymph node metastases (2006) Clin. Cancer Res., 12, pp. 5741-5745; Li, Y., Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes Relevance to diabetes and inflammation (2008) J. Biol. Chem., 283, pp. 26771-26781; Li, Y., The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate (2009) J. Biol. Chem., 284, pp. 34283-34295; Louie, M.C., Androgen-induced recruitment of RNA polymerase II to a nuclear receptor-p160 coactivator complex (2003) Proc. Natl. Acad. Sci. U. S. A., 100, pp. 2226-2230; Lu, T., Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65 (2010) Proc. Natl. Acad. Sci. U. S. A., 107, pp. 46-51; Malinowska, K., Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor (2009) Endocr. Relat. Cancer, 16, pp. 155-169; Marango, J., The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor (2008) Blood, 111, pp. 3145-3154; Martinez-Garcia, E., The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells (2011) Blood, 117, pp. 211-220; Min, J., An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factorkappaB (2010) Nat. Med., 16, pp. 286-294; Nadiminty, N., Aberrant activation of the androgen receptor by NF-kappaB2/p52 in prostate cancer cells (2010) Cancer Res, 70, pp. 3309-3319; Ndlovu, M.N., Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutivetranscription across the interleukin-6 gene promoter in metastatic breast cancer cells (2009) Mol. Cell. Biol., 29, pp. 5488-5504; Nimura, K., A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome (2009) Nature, 460, pp. 287-291; Niu, Y., Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails (2010) Oncogene, 29, pp. 3593-3604; Norris, J.D., The homeodomain protein HOXB13 regulates the cellular response to androgens (2009) Mol. Cell, 36, pp. 405-416; Nowak, D.E., RelA Ser276 phosphorylation is required for activation of a subset of NF-kappaB-dependent genes by recruiting cyclindependent kinase 9/cyclin T1 complexes (2008) Mol. Cell. Biol., 28, pp. 3623-3638; Pei, H., MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites (2011) Nature, 470, pp. 124-128; Perkins, N.D., The diverse and complex roles of NF-kappaB subunits in cancer (2012) Nat. Rev. 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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. © 2012, American Society for Microbiology.

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. © 2012, American Society for Microbiology.

KW - acyltransferase

KW - cyclin D

KW - histone methyltransferase

KW - histone methyltransferase mmset

KW - histone methyltransferase nsd2

KW - immunoglobulin enhancer binding protein

KW - interleukin 6

KW - interleukin 8

KW - methyltransferase

KW - protein bcl 2

KW - protein p300

KW - survivin

KW - tumor necrosis factor alpha

KW - unclassified drug

KW - vasculotropin A

KW - acetylation

KW - article

KW - autocrine effect

KW - cancer cell

KW - castration resistant prostate cancer

KW - cell proliferation

KW - cell survival

KW - chromatin

KW - controlled study

KW - enzyme activity

KW - gene targeting

KW - human

KW - human cell

KW - positive feedback

KW - priority journal

KW - promoter region

KW - protein expression

KW - protein interaction

KW - tumor growth

KW - Acetylation

KW - Animals

KW - Autocrine Communication

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cell Survival

KW - Chromatin

KW - Cyclin D

KW - Gene Expression Regulation, Neoplastic

KW - Histone-Lysine N-Methyltransferase

KW - Histones

KW - Humans

KW - Inhibitor of Apoptosis Proteins

KW - Interleukin-6

KW - Interleukin-8

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Neoplasm Transplantation

KW - NF-kappa B

KW - p300-CBP Transcription Factors

KW - Promoter Regions, Genetic

KW - Prostatic Neoplasms

KW - Proto-Oncogene Proteins c-bcl-2

KW - Repressor Proteins

KW - RNA Interference

KW - RNA, Small Interfering

KW - Signal Transduction

KW - Transplantation, Heterologous

KW - Tumor Necrosis Factor-alpha

KW - Vascular Endothelial Growth Factor A

U2 - 10.1128/MCB.00204-12

DO - 10.1128/MCB.00204-12

M3 - Article

VL - 32

SP - 3121

EP - 3131

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 15

ER -