title: Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression.
abstract: 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.
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Muhammad Tariq
authors.initials: MT
authors.lastname: Saeed
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Islamabad, Pakistan; School of Computer Science and IT, Stratford University, VA, United States.
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou , China.
authors.forename: Shahzina
authors.initials: S
authors.lastname: Kanwal
authors.affiliation: Department of Oncology, Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute , Detroit , MI , United States.
authors.forename: Andreana N
authors.initials: AN
authors.lastname: Holowatyj
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Iftikhar A
authors.initials: IA
authors.lastname: Sheikh
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Rehan
authors.initials: R
authors.lastname: Zafar Paracha
authors.affiliation: School of Electrical Engineering and Computer Science (SEECS), National University of Sciences and Technology (NUST), Islamabad, Pakistan; College of Computer Science and Information Technology, University of Dammam, Al Khobar, Kingdom of Saudi Arabia.
authors.forename: Aamir
authors.initials: A
authors.lastname: Shafi
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Amnah
authors.initials: A
authors.lastname: Siddiqa
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Zurah
authors.initials: Z
authors.lastname: Bibi
authors.affiliation: Research Centre for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Mukaram
authors.initials: M
authors.lastname: Khan
authors.affiliation: Atta-ur-Rehman School of Applied Bio-science (ASAB), National University of Sciences and Technology (NUST) , Islamabad , Pakistan.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
keywords: Biological regulatory networks (BRNs); Cancer; Hexosamine biosynthetic pathway; Model checking; O-GlcNAcylation; OGT; Qualitative modeling; René Thomas; SMBioNet