Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression

PeerJ

article

Muhammad Tariq Saeed¹  Jamil Ahmad¹  Shahzina Kanwal³  Andreana N. Holowatyj⁴  Iftikhar A. Sheikh¹  Rehan Zafar Paracha¹  Aamir Shafi⁵  Amnah Siddiqa¹  Zurah Bibi¹  Mukaram Khan¹  Amjad Ali⁷ 

[1] Research Centre for Modeling and Simulation ,(RCMS), National University of Sciences and Technology;School of Computer Science and IT, Stratford University;Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences;Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute;School of Electrical Engineering and Computer Science ,(SEECS), National University of Sciences and Technology;College of Computer Science and Information Technology, University of Dammam;Atta-ur-Rehman School of Applied Bio-science ,(ASAB), National University of Sciences and Technology

关键词: Biological regulatory networks (BRNs);    René Thomas;    Qualitative modeling;    Model checking;    Cancer;    Hexosamine biosynthetic pathway;    O-GlcNAcylation;    OGT;    SMBioNet;   

DOI  :  10.7717/peerj.2348

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

The alteration of glucose metabolism, through increased uptake of glucose and glutamine addiction, is essential to cancer cell growth and invasion. Increased flux of glucose through the Hexosamine Biosynthetic Pathway (HBP) drives increased cellular O-GlcNAcylation (hyper-O-GlcNAcylation) and contributes to cancer progression by regulating key oncogenes. However, the association between hyper-O-GlcNAcylation and activation of these oncogenes remains poorly characterized. Here, we implement a qualitative modeling framework to analyze the role of the Biological Regulatory Network in HBP activation and its potential effects on key oncogenes. Experimental observations are encoded in a temporal language format and model checking is applied to infer the model parameters and qualitative model construction. Using this model, we discover step-wise genetic alterations that promote cancer development and invasion due to an increase in glycolytic flux, and reveal critical trajectories involved in cancer progression. We compute delay constraints to reveal important associations between the production and degradation rates of proteins. O-linked N-acetylglucosamine transferase (OGT), an enzyme used for addition of O-GlcNAc during O-GlcNAcylation, is identified as a key regulator to promote oncogenesis in a feedback mechanism through the stabilization of c-Myc. Silencing of the OGT and c-Myc loop decreases glycolytic flux and leads to programmed cell death. Results of network analyses also identify a significant cycle that highlights the role of p53-Mdm2 circuit oscillations in cancer recovery and homeostasis. Together, our findings suggest that the OGT and c-Myc feedback loop is critical in tumor progression, and targeting these mediators may provide a mechanism-based therapeutic approach to regulate hyper-O-GlcNAcylation in human cancer.

【 授权许可】

CC BY