Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
Sci Rep. 2017 Sep 6;7(1):10607. doi: 10.1038/s41598-017-10886-x.
Aberrant metabolism in hexosamine biosynthetic pathway (HBP) has been observed in several cancers, affecting cellular signaling and tumor progression. However, the role of O-GlcNAcylation, a post-translational modification through HBP flux, in apoptosis remains unclear. Here, we found that hyper-O-GlcNAcylation in lung carcinoma cells by O-GlcNAcase inhibition renders the cells to apoptosis resistance to cisplatin (CDDP). Profiling of various key regulatory proteins revealed an implication of either p53 or c-Myc in the apoptosis regulation by O-GlcNAcylation, independent of p53 status. Using co-immunoprecipitation and correlation analyses, we found that O-GlcNAcylation of p53 under certain cellular contexts, i.e. high p53 activation, promotes its ubiquitin-mediated proteasomal degradation, resulting in a gain of oncogenic and anti-apoptotic functions. By contrast, O-GlcNAcylation of c-Myc inhibits its ubiquitination and subsequent proteasomal degradation. Gene manipulation studies revealed that O-GlcNAcylation of p53/c-Myc is in part a regulator of CDDP-induced apoptosis. Accordingly, we classified CDDP resistance by hyper-O-GlcNAcylation in lung carcinoma cells as either p53 or c-Myc dependence based on their molecular targets. Together, our findings provide novel mechanisms for the regulation of lung cancer cell apoptosis that could be important in understanding clinical drug resistance and suggest O-GlcNAcylation as a potential target for cancer therapy.
己糖胺生物合成途径（HBP）中的代谢异常在多种癌症中都有观察到，影响细胞信号转导和肿瘤进展。然而，HBP 流量的翻译后修饰 O-GlcNAcylation 在细胞凋亡中的作用尚不清楚。在这里，我们发现通过 O-GlcNAcase 抑制使肺癌细胞中超 O-GlcNAcylation 导致细胞对顺铂（CDDP）的凋亡抵抗。对各种关键调节蛋白的分析表明，O-GlcNAcylation 通过 p53 或 c-Myc 调节细胞凋亡，与 p53 状态无关。通过共免疫沉淀和相关性分析，我们发现高 p53 激活等特定细胞环境下 p53 的 O-GlcNAcylation 促进其泛素介导的蛋白酶体降解，从而获得致癌和抗凋亡功能。相比之下，c-Myc 的 O-GlcNAcylation 抑制其泛素化和随后的蛋白酶体降解。基因操作研究表明，p53/c-Myc 的 O-GlcNAcylation 部分是 CDDP 诱导细胞凋亡的调节因子。因此，我们根据它们的分子靶标，将肺癌细胞中高 O-GlcNAcylation 引起的 CDDP 耐药性分为 p53 或 c-Myc 依赖性。总之，我们的研究结果为肺癌细胞凋亡的调控提供了新的机制，这对于理解临床耐药性可能很重要，并表明 O-GlcNAcylation 可能是癌症治疗的潜在靶点。
