文章：

NF-κB p65亚基S550和S551位点新型O-GlcNAc修饰在胰腺癌中的关键作用

Critical Role of Novel O-GlcNAcylation of S550 and S551 on the p65 Subunit of NF-κB in Pancreatic Cancer

原文发布日期：27 September 2023

DOI: 10.3390/cancers15194742

类型: Article

开放获取: 是

英文摘要：

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a mere 5-year survival of ~10%. This highlights the urgent need for innovative treatment options for PDAC patients. The nuclear factor κB (NF-κB) is a crucial transcription factor that is constitutively activated in PDAC. It mediates the transcription of oncogenic and inflammatory genes that facilitate multiple PDAC phenotypes. Thus, a better understanding of the mechanistic underpinnings of NF-κB activation holds great promise for PDAC diagnosis and effective therapeutics. Here, we report a novel finding that the p65 subunit of NF-κB is O-GlcNAcylated at serine 550 and 551 upon NF-κB activation. Importantly, the overexpression of either serine-to-alanine (S-A) single mutant (S550A or S551A) or double mutant (S550A/S551A) of p65 in PDAC cells impaired NF-κB nuclear translocation, p65 phosphorylation, and transcriptional activity, independent of IκBα degradation. Moreover, the p65 mutants downregulate a category of NF-κB-target genes, which play a role in perpetuating major cancer hallmarks. We further show that overexpression of the p65 mutants inhibited cellular proliferation, migration, and anchorage-independent growth of PDAC cells compared to WT-p65. Collectively, we discovered novel serine sites of p65 O-GlcNAcylation that drive NF-κB activation and PDAC phenotypes, thus opening new avenues by inhibiting the NF-κB O-GlcNAcylation enzyme, O-GlcNAc transferase (OGT), for PDAC treatment in the future.

摘要翻译： 

胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，其五年生存率仅为10%左右，这凸显了为PDAC患者寻找创新治疗方案的迫切需求。核因子κB（NF-κB）是一种关键的转录因子，在PDAC中持续激活，介导致癌基因和炎症基因的转录，从而促进多种PDAC表型的形成。因此，深入理解NF-κB激活的分子机制对于PDAC的诊断和有效治疗具有重要意义。本研究首次发现，在NF-κB激活过程中，其p65亚基的丝氨酸550和551位点会发生O-GlcNAc糖基化修饰。重要的是，在PDAC细胞中过表达p65的丝氨酸-丙氨酸单突变体（S550A或S551A）或双突变体（S550A/S551A）会损害NF-κB的核转位、p65磷酸化及其转录活性，且这一过程不依赖于IκBα的降解。此外，这些p65突变体下调了一组NF-κB靶基因的表达，这些基因在维持癌症主要特征中发挥重要作用。进一步研究表明，与野生型p65相比，过表达p65突变体能抑制PDAC细胞的增殖、迁移和非锚定依赖性生长。综上所述，我们发现了驱动NF-κB激活和PDAC表型的新型p65 O-GlcNAc糖基化丝氨酸位点，这为未来通过抑制NF-κB O-GlcNAc糖基化酶——O-GlcNAc转移酶（OGT）来治疗PDAC开辟了新途径。

原文链接：

Critical Role of Novel O-GlcNAcylation of S550 and S551 on the p65 Subunit of NF-κB in Pancreatic Cancer