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Crosstalk between hypoxia-sensing ULK1/2 and YAP-driven glycolysis fuels pancreatic ductal adenocarcinoma development.

ABSTRACT: Autophagy and glycolysis are two catabolic processes that manipulate pancreatic ductal adenocarcinoma (PDAC) development in response to hypoxia sensing, yet the underlying mechanism of how they are interlinked remain elusive. Methods: The functional roles of Unc-51 like kinase 1 and 2 (ULK1/2) in pyruvate kinase M2 (PKM2) transcription and glycolysis under hypoxia were assessed by chromatin immunoprecipitation, luciferase reporter, glucose consumption and lactate production assay. Co-immunoprecipitation, cellular ubiquitination, His-pulldown, in vitro protein kinase assay, immunofluorescence, immunohistochemistry, CRISPR technology, in silico studies were adopted to determine the molecular mechanism. Correlation analyses were performed in KPC (Pdx1-Cre; LSL-Kras^G12D/+; Trp53^fl/+) mice and clinical samples from PDAC patients. Therapeutic potential of ULK1/2 inhibitor and 2-deoxyglucose (2-DG) or 3-bromopyruvate (3-BP) was evaluated in cell-derived xenograft (CDX) and the patient-derived xenograft (PDX) models of nude mice. Results: ULK1/2, but not ULK3, augments hypoxic glycolysis in PDAC cells mediated by PKM2 independent of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice. ULK1/2 is positively correlated with YAP and PKM2 in tumor tissues from KPC mice and clinical samples from PDAC patients. Pharmacological deactivation of ULK1/2 potentiates the antineoplastic efficacy of 2-DG and 3-BP in CDX and PDX models. Conclusion: Our findings underscore the Ser227 autophosphorylation-dependent nuclear YAP stabilization as a central node that couples ULK1/2-initiated autophagy to hypoxic glycolysis during PDAC development and propose that targeting ULK1/2 combined with 2-DG or 3-BP might be a feasible therapeutic strategy against PDAC.

SUBMITTER: Jia Y

PROVIDER: S-EPMC8326115 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Although progress has been made in the treatment of PDAC, its prognosis remains unsatisfactory. This study aimed to develop novel prognostic genes related to glycolysis in PDAC and to apply these genes to new risk stratification. Methods: In this study, based on the Cancer Genome Atlas (TCGA) PAAD cohort, the expression level of glycolysis-related gene at mRNA level in PAAD and its relationship with prognosis were analyzed. Non-negative matrix decomposition (NMF) clustering was used to cluster PDAC patients according to glycolytic genes. Prognostic glycolytic genes, screened by univariate Cox analysis and LASSO regression analysis were established to calculate risk scores. The differentially expressed genes (DEGs) in the high-risk group and the low-risk group were analyzed, and the signal pathway was further enriched to analyze the correlation between glycolysis genes. In addition, based on RNA-seq data, CIBERSORT was used to evaluate the infiltration degree of immune cells in PDAC samples, and ESTIMATE was used to calculate the immune score of the samples. Results: A total of 319 glycolysis-related genes were retrieved, and all PDAC samples were divided into two clusters by NMF cluster analysis. Survival analysis showed that PDAC patients in cluster 1 had shorter survival time and worse prognosis compared with cluster 2 samples (P < 0.001). A risk prediction model based on 11 glycolysis genes was constructed, according to which patients were divided into two groups, with significantly poorer prognosis in high-risk group than in low-risk group (P < 0.001). Both internal validation and external dataset validation demonstrate good predictive ability of the model (AUC = 0.805, P < 0.001; AUC = 0.763, P < 0.001). Gene aggregation analysis showed that DEGs highly expressed in high-risk group were mainly concentrated in the glycolysis level, immune status, and tumor cell proliferation, etc. In addition, the samples in high-risk group showed immunosuppressed status and infiltrated by relatively more macrophages and less CD8+T cell. Conclusions: These findings suggested that the gene signature based on glycolysis-related genes had potential diagnostic, therapeutic, and prognostic value for PDAC.

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Crosstalk between hypoxia-sensing ULK1/2 and YAP-driven glycolysis fuels pancreatic ductal adenocarcinoma development.

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