Application of Multi-Omics and Chemoinformatics to Analyze Oncogenic Roles and Assess Potential Inhibitors for NCAPG

Abstract

NonSMC Condensin I complex subunit G (NCAPG) is classified as a mitosis-related chromosomal condensation protein with several reports mentioning its oncogenic roles in different types of human cancers. Despite these reports, there is a lack of a comprehensive analysis of that gene in a panel of human tumors in addition to the need to develop special inhibitors to NCAPG that could potentially act as antitumor drugs. The current study initiated with the assessment of a panel of human cancers for NCAPG expression in cancerous tissues versus normal ones and the consequences of that expression on tumor stage, grade, metastasis and patient survival. Next, we evaluated the protein level plus the differential phosphorylation and methylation of NCAPG in human tumors in comparison to controls. Additionally, an enrichment analysis of NCAPG and its correlated proteins was performed to predict the molecular mechanism of NCAPG oncogenesis. Here we revealed that NCAPG is highly expressed in a list of human tumors and that was positively correlated with tumor stage, grade and metastasis which was reflected negatively on the clinical outcome. Additionally, NCAPG was hyperphosphorylated and hypomethylated in cancerous tissue which allowed for its overexpression and hyperactivation. Furthermore, NCAPG protein interacts with several proteins that are responsible for cell division and cell cycle in a manner that could explain uncontrolled cell proliferation and cancer induction. The druggability of the NCAPG-Kleisin subcomplex has been investigated through a molecular docking-coupled dynamics simulation study. Several small molecules, particularly the atropisomeric alkaloid Michellamine A, have been identified as potential inhibitors downgrading the protein–protein interactions across explicit molecular dynamics simulations. Collectively, the current study demonstrates the oncogenic behavior of NCAPG at multiple levels with the nomination of several inhibitors as potential antitumor agents.