Histone methyltransferase NSD2/MMSET mediates constitutive NF-κB signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop.
Constitutive NF-κB 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-κB by directly interacting with NF-κB 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-κB 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-κB and acetyltransferase p300 and histone hyperacetylation. Importantly, NSD2 is overexpressed in prostate cancer tumors, and its overexpression correlates with NF-κB activation. Furthermore, NSD2 expression is strongly induced by tumor necrosis factor alpha (TNF-α) and IL-6 via NF-κB and plays a crucial role in tumor growth. These results identify NSD2 to be a key chromatin regulator of NF-κB and mediator of the cytokine autocrine loop for constitutive NF-κB activation and emphasize the important roles played by NSD2 in cancer cell proliferation and survival and tumor growth.
UC Davis Cancer Center/Basic Sciences, University of California at Davis, Sacramento, California, USA.
Ping
P
Yang
Linlang
L
Guo
Zhijian J
ZJ
Duan
Clifford G
CG
Tepper
Ling
L
Xue
Xinbin
X
Chen
Hsing-Jien
HJ
Kung
Allen C
AC
Gao
June X
JX
Zou
Hong-Wu
HW
Chen
D000107:Acetylation; D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism*; D056741:Cyclin D / Q000096:biosynthesis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D006657:Histones / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D002843:Chromatin; D056741:Cyclin D; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C107489:BIRC5 protein, human; C419586:NSD2 protein, human