胰腺癌（PC）发病机制的混杂因素之一是高血糖。高血糖 (HG) 影响 PC 严重程度的分子机制尚不清楚。我们的研究深入探讨了肝癌 (HULC) 中高度上调的 lncRNA 的影响及其与 yes 相关蛋白 (YAP) 的相互作用在 HG 诱导条件下调节胰腺导管腺癌细胞 (PDAC) 的命运。 PDAC细胞在正常或HG条件下培养。随后我们测量了 HG 对 PDAC 细胞活力、迁移潜力和耐药特性的影响。通过生物信息学分析和湿实验室功能验证，将被认为在 PC 和糖尿病中失调的 lncRNA 列入候选名单。HG 导致 PDAC 细胞增殖和药物耐药性增强。经过生物信息学分析，HULC 被确定为主要失调的 lncRNA 之一。人们发现 HULC 通过 YAP 启动子上的选择性组蛋白修饰来调节有效转录调节因子 - YAP 的表达。 siRNA 介导的 HULC 消融导致 YAP 转录活性同时降低。重要的是，HULC 和 YAP 被发现协同调节细胞稳态过程自噬，从而在 PDAC 细胞中灌输耐药性和增殖潜力。此外，自噬或 YAP 的抑制导致 HULC 水平下降，表明存在调节间反馈循环。我们观察到 HG 触发 PDAC 细胞的攻击特性。从机制上讲，lncRNA HULC 的上调导致 YAP 的激活和自噬的差异调节，从而增加 PDAC 细胞的增殖。抑制 HULC 和 YAP 可能代表 PDAC 的一种新的治疗策略。此外，这项研究描绘了 PDAC 发病机制中 HULC、YAP 和自噬之间复杂的分子相互作用。© 2024 作者。 《细胞生物学》由 Wiley‐VCH GmbH 代表法国显微镜学会和法国细胞生物学学会出版。

One of the confounding factors in pancreatic cancer (PC) pathogenesis is hyperglycemia. The molecular mechanism by which high glucose (HG) influences PC severity is poorly understood. Our investigation delved into the impact of lncRNA highly upregulated in liver cancer (HULC) and its interaction with yes-associated protein (YAP) in regulating the fate of pancreatic ductal adenocarcinoma cells (PDAC) under HG-induced conditions. PDAC cells were cultured under normal or HG conditions. We thereafter measured the effect of HG on the viability of PDAC cells, their migration potential and drug resistance properties. The lncRNAs putatively dysregulated in PC and diabetes were shortlisted by bioinformatics analysis followed by wet lab validation of function.HG led to enhanced proliferation and drug refractoriness in PDAC cells. HULC was identified as one of the major deregulated lncRNAs following bioinformatics analysis. HULC was found to regulate the expression of the potent transcriptional regulator - YAP through selective histone modifications at the YAP promoter. siRNA-mediated ablation of HULC resulted in a concurrent decrease in YAP transcriptional activity. Importantly, HULC and YAP were found to co-operatively regulate the cellular homeostatic process autophagy, thus inculcating drug resistance and proliferative potential in PDAC cells. Moreover, inhibition of autophagy or YAP led to a decrease in HULC levels, suggesting the existence of an inter-regulatory feedback loop.We observed that HG triggers aggressive properties in PDAC cells. Mechanistically, up-regulation of lncRNA HULC resulted in activation of YAP and differential regulation of autophagy coupled to increased proliferation of PDAC cells.Inhibition of HULC and YAP may represent a novel therapeutic strategy for PDAC. Furthermore, this study portrays the intricate molecular interplay between HULC, YAP and autophagy in PDAC pathogenesis.© 2024 The Author(s). Biology of the Cell published by Wiley‐VCH GmbH on behalf of Société Française des Microscopies and Société Biologie Cellulaire de France.