PAF1/HIF1α axis rewires the glycolytic metabolism to fuel aggressiveness of pancreatic cancer.

IF 6 3区医学 Q1 CELL BIOLOGY

Cancer & Metabolism Pub Date : 2024-09-06 DOI:10.1186/s40170-024-00354-2

Ayoola O Ogunleye, Neelanjana Gayen, Sanchita Rauth, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Zahraa W Alsafwani, Jesse L Cox, Surinder K Batra, Moorthy P Ponnusamy

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引用次数: 0

Abstract

Background: PAF1/PD2 deregulation contributes to tumorigenesis, drug resistance, and cancer stem cell maintenance in Pancreatic Cancer (PC). Recent studies demonstrate that metabolic reprogramming plays a role in PC progression, but the mechanism is poorly understood. Here, we focused on examining the role of PAF1/PD2 in the metabolic rewiring of PC.

Methods: Cell lines were transfected with shRNAs to knockdown PAF1/PD2. Metabolic genes regulated by PAF1/PD2 were identified by qPCR/western blot, and metabolic assays were performed. Immunoprecipitations/ChIP were performed to identify PAF1/PD2 protein partners and confirm PAF1/HIF1α sub-complex binding to LDHA.

Results: PAF1 and LDHA showed progressively increased expression in human pancreatic tumor sections. Aerobic glycolysis genes were downregulated in PAF1-depleted PC cells. Metabolic assays indicated a decreased lactate production and glucose uptake in knockdown cells. Furthermore, PAF1/PD2 depletion showed a reduced glycolytic rate and increased oxidative phosphorylation by ECAR and OCR analysis. Interestingly, we identified that HIF1α interacts and co-localizes with PAF1, specifically in PC cells. We also observed that the PAF1/PD2-HIF1α complex binds to the LDHA promoter to regulate its expression, reprogramming the metabolism to utilize the aerobic glycolysis pathway preferentially.

Conclusion: Overall, the results indicate that PAF1/PD2 rewires PC metabolism by interacting with HIF1α to regulate the expression of LDHA.

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PAF1/HIF1α轴重构了糖代谢，助长了胰腺癌的侵袭性。

背景：PAF1/PD2失调导致了胰腺癌（PC）的肿瘤发生、耐药性和癌症干细胞的维持。最近的研究表明，代谢重编程在胰腺癌的进展中起着一定的作用，但对其机制还不甚了解。在此，我们重点研究了 PAF1/PD2 在 PC 代谢重构中的作用：方法：用 shRNA 转染细胞系以敲除 PAF1/PD2。方法：用 shRNAs 转染细胞株以敲除 PAF1/PD2，通过 qPCR/western 印迹鉴定受 PAF1/PD2 调控的代谢基因，并进行代谢测定。通过免疫沉淀/ChIP鉴定PAF1/PD2蛋白伴侣并确认PAF1/HIF1α亚复合物与LDHA的结合：结果：PAF1和LDHA在人胰腺肿瘤切片中的表达逐渐增加。在 PAF1 缺失的 PC 细胞中，有氧糖酵解基因下调。代谢测定显示，基因敲除细胞的乳酸生成和葡萄糖摄取均有所减少。此外，通过 ECAR 和 OCR 分析，PAF1/PD2 缺失显示糖酵解率降低，氧化磷酸化增加。有趣的是，我们发现 HIF1α 与 PAF1 相互作用并共定位，特别是在 PC 细胞中。我们还观察到，PAF1/PD2-HIF1α复合物与LDHA启动子结合，调控其表达，使新陈代谢重编程，优先利用有氧糖酵解途径：总之，研究结果表明，PAF1/PD2 通过与 HIF1α 相互作用来调节 LDHA 的表达，从而重塑了 PC 的新陈代谢。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer & Metabolism Multiple-

自引率

1.70%

发文量

审稿时长

14 weeks

期刊介绍： Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.