Kinless hubs are potential target genes in prostate cancer network

• Published in: Genomics (San Diego, Calif.) Calif.), 2020-11, Vol.112 (6), p.5227-5239
• Main Authors: Mangangcha, Irengbam Rocky, Malik, Md. Zubbair, Kucuk, Omer, Ali, Shakir, Singh, R.K. Brojen
• Format: Article
• Language: English
• Subjects: Centrality lethality rule; cost effectiveness; data collection; death; energy; gene expression; genes; Hubs; information processing; Key disease genes; Network theory; patients; Prostate Cancer; prostatic neoplasms; protein-protein interactions; Systems biology
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/j.ygeno.2020.09.033

Complex disease networks can be studied successfully using network theoretical approach which helps in finding key disease genes and associated disease modules. We studied prostate cancer (PCa) protein-protein interaction (PPI) network constructed from patients' gene expression datasets and found that the network exhibits hierarchical scale free topology which lacks centrality lethality rule. Knockout experiments of the sets of leading hubs from the network leads to transition from hierarchical (HN) to scale free (SF) topology affecting network integration and organization. This transition, HN → SF, due to removal of significant number of the highest degree hubs, leads to relatively decrease in information processing efficiency, cost effectiveness of signal propagation, compactness, clustering of nodes and energy distributions. A systematic transition from a diassortative PCa PPI network to assortative networks after the removal of top 50 hubs then again reverting to disassortativity nature on further removal of the hubs was also observed indicating the dominance of the largest hubs in PCa network intergration. Further, functional classification of the hubs done by using within module degrees and participation coefficients for PCa network, and leading hubs knockout experiments indicated that kinless hubs serve as the basis of establishing links among constituting modules and heterogeneous nodes to maintain network stabilization. We, then, checked the essentiality of the hubs in the knockout experiment by performing Fisher's exact test on the hubs, and showed that removal of kinless hubs corresponded to maximum lethality in the network. However, excess removal of these hubs essentially may cause network breakdown. •The study showed that the PCa PPI network follows hierarchical scale free network topology lacking centrality lethality rule.•From knockout experiment, the removing of leading hubs results in a systemic transition from a hierarchical scale free network to scale free topology and then to Network breakdown regime on excessive removal of hubs.•The network topology transition behavior corresponded with losing its self organization and compactness.•The classification of the hubs to modular kinless, connector and peripheral hubs on their participation ratios (Pi) and within module degree z score (Zi) showed that the kinless hubs take major responsibility to regulate the PCa PPI network and their removal corresponded with maximum lethality on the networ