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Multilevel regulation of NF-kappa B signaling by NSD2 suppresses Kras-driven pancreatic tumorigenesis

Feng, W.; Niu, N.; Lu, P.; Rao, H.; Chen, Z.; Zhang, W.; Ma, C.; Liu, C.; Xu, Y.; Gao, W.-Q.; Xue, J.; Li, L.

2023-09-14 cancer biology
10.1101/2023.09.11.557111 bioRxiv
Show abstract

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase which has been reported to play a crucial role in promoting tumorigenesis. Here, we demonstrate that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. Low level of NSD2 indicates aggressive feature of PDAC. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of I{kappa}B, which inhibits the phosphorylation of p65 and NF-{kappa}B nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-{kappa}B transcriptional activity. Furthermore, inhibition of NF-{kappa}B signaling relieves the symptoms of Nsd2-deficient mice. Together, our study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study contributes to understanding the pathogenesis of pancreatic tumorigenesis and identifies a novel negative regulator of NF-{kappa}B signaling.

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