Ayoola O Ogunleye, Neelanjana Gayen, Sanchita Rauth, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Zahraa W Alsafwani, Jesse L Cox, Surinder K Batra, Moorthy P Ponnusamy
{"title":"PAF1/HIF1α axis rewires the glycolytic metabolism to fuel aggressiveness of pancreatic cancer.","authors":"Ayoola O Ogunleye, Neelanjana Gayen, Sanchita Rauth, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Zahraa W Alsafwani, Jesse L Cox, Surinder K Batra, Moorthy P Ponnusamy","doi":"10.1186/s40170-024-00354-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Overall, the results indicate that PAF1/PD2 rewires PC metabolism by interacting with HIF1α to regulate the expression of LDHA.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380429/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer & Metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40170-024-00354-2","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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.
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.