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PAF1/HIF1α轴重塑糖酵解代谢以助长胰腺癌的侵袭性。

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

作者信息

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

机构信息

Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, 985870, USA.

Department of Pathology and Microbiology, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.

出版信息

Cancer Metab. 2024 Sep 6;12(1):26. doi: 10.1186/s40170-024-00354-2.

DOI:10.1186/s40170-024-00354-2
PMID:39242538
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11380429/
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.

摘要

背景

PAF1/PD2失调促进胰腺癌（PC）的肿瘤发生、耐药性及癌症干细胞维持。近期研究表明代谢重编程在PC进展中起作用，但其机制尚不清楚。在此，我们着重研究PAF1/PD2在PC代谢重塑中的作用。

方法

用短发夹RNA转染细胞系以敲低PAF1/PD2。通过定量聚合酶链反应/蛋白质免疫印迹法鉴定受PAF1/PD2调控的代谢基因，并进行代谢分析。进行免疫沉淀/染色质免疫沉淀以鉴定PAF1/PD2蛋白伴侣，并确认PAF1/缺氧诱导因子1α亚复合物与乳酸脱氢酶A（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。代谢分析表明敲低细胞中乳酸生成减少和葡萄糖摄取降低。此外，通过细胞外酸化率和氧消耗率分析，PAF1/PD2缺失显示糖酵解速率降低和氧化磷酸化增加。有趣的是，我们发现缺氧诱导因子1α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-缺氧诱导因子1α复合物与LDHA启动子结合以调节其表达，将代谢重编程以优先利用有氧糖酵解途径。

结论

总体而言，结果表明PAF1/PD2通过与缺氧诱导因子1α相互作用调节LDHA的表达来重塑PC代谢。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/60a801e79be7/40170_2024_354_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/14626aa4f197/40170_2024_354_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/35e046c2a7e5/40170_2024_354_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/df7da816c998/40170_2024_354_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/1c2bddd9d45d/40170_2024_354_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/8e7020388168/40170_2024_354_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/60a801e79be7/40170_2024_354_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/14626aa4f197/40170_2024_354_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/35e046c2a7e5/40170_2024_354_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/df7da816c998/40170_2024_354_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/1c2bddd9d45d/40170_2024_354_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/8e7020388168/40170_2024_354_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e05/11380429/60a801e79be7/40170_2024_354_Fig6_HTML.jpg

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本文引用的文献

1
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Stem Cells. 2023 May 15;41(5):417-430. doi: 10.1093/stmcls/sxad017.
2
Elevated PAF1-RAD52 axis confers chemoresistance to human cancers.PAF1-RAD52 轴升高赋予人类癌症化疗耐药性。
Cell Rep. 2023 Feb 28;42(2):112043. doi: 10.1016/j.celrep.2023.112043. Epub 2023 Jan 28.
3
Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma.糖酵解型胰腺导管腺癌的功能性非侵入性检测
Cancer Metab. 2022 Dec 9;10(1):24. doi: 10.1186/s40170-022-00298-5.
4
PAF1 cooperates with YAP1 in metaplastic ducts to promote pancreatic cancer.PAF1 与 YAP1 在化生导管中合作促进胰腺癌。
Cell Death Dis. 2022 Oct 1;13(10):839. doi: 10.1038/s41419-022-05258-x.
5
Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.Sirt5 缺失导致的代谢重构促进 Kras 诱导的胰腺癌进展。
Gastroenterology. 2021 Nov;161(5):1584-1600. doi: 10.1053/j.gastro.2021.06.045. Epub 2021 Jul 8.
6
Up-down regulation of HIF-1α in cancer progression.HIF-1α 在癌症进展中的上下调节。
Gene. 2021 Sep 25;798:145796. doi: 10.1016/j.gene.2021.145796. Epub 2021 Jun 25.
7
A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival.KDM4A-PAF1 介导的表观基因组网络对急性髓系白血病细胞自我更新和存活至关重要。
Cell Death Dis. 2021 Jun 3;12(6):573. doi: 10.1038/s41419-021-03738-0.
8
The HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis.HIF-1α 反义长非编码 RNA 驱动 HIF-1α 介导的反式激活和糖酵解的正反馈回路。
Nat Commun. 2021 Feb 26;12(1):1341. doi: 10.1038/s41467-021-21535-3.
9
Targeting hypoxic tumor microenvironment in pancreatic cancer.针对胰腺癌的缺氧肿瘤微环境。
J Hematol Oncol. 2021 Jan 13;14(1):14. doi: 10.1186/s13045-020-01030-w.
10
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Gastroenterology. 2020 Nov;159(5):1898-1915.e6. doi: 10.1053/j.gastro.2020.07.053. Epub 2020 Aug 8.