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

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.