Investigating core genetic-and-epigenetic cell cycle networks for stemness and carcinogenic mechanisms, and cancer drug design using big database mining and genome-wide next-generation sequencing data

Abstract

Recent studies have demonstrated that cell cycle plays a central role in development and carcinogenesis. Thus, the use of big databases and genome-wide high-throughput data to unravel the genetic and epigenetic mechanisms underlying cell cycle progression in stem cells and cancer cells is a matter of considerable interest.Real genetic-and-epigenetic cell cycle networks (GECNs) of embryonic stem cells (ESCs) and HeLa cancer cells were constructed by applying system modeling, system identification, and big database mining to genome-wide next-generation sequencing data. Real GECNs were then reduced to core GECNs of HeLa cells and ESCs by applying principal genome-wide network projection. In this study, we investigated potential carcinogenic and stemness mechanisms for systems cancer drug design by identifying common core and specific GECNs between HeLa cells and ESCs. Integrating drug database information with the specific GECNs of HeLa cells could lead to identification of multiple drugs for cervical cancer treatment with minimal side-effects on the genes in the common core. We found that dysregulation of miR-29C, miR-34A, miR-98, and miR-215; and methylation of ANKRD1, ARID5B, CDCA2, PIF1, STAMBPL1, TROAP, ZNF165, and HIST1H2AJ in HeLa cells could result in cell proliferation and anti-apoptosis through NFκB, TGF-β, and PI3K pathways. We also identified 3 drugs, methotrexate, quercetin, and mimosine, which repressed the activated cell cycle genes, ARID5B, STK17B, and CCL2, in HeLa cells with minimal side-effects.

Analysis of the Expression of Cell Division Cycle-Associated Genes and Its Prognostic Significance in Human Lung Carcinoma: A Review of the Literature Databases

“…CDCA2 acts as the PP1c expression regulator, which inhibits the activation of DNA damage response [8,9]. Recent research results demonstrate that CDCA2 methylation in HeLa cells promotes cell proliferation and suppresses apoptosis [26]. Additionally, CDCA2 overexpression promotes the proliferation of CRC cells and oral squamous cell carcinoma (OSCC) cells [27,28].…”

Epigenetic basis of hepatocellular carcinoma: A network-based integrative meta-analysis

“…These included HIST1H2AJ , which is a histone-coding cell cycle gene previously also identified as hypermethylated in patient lung adenocarcinoma samples[ 37 ] and head and neck squamous cell carcinomas[ 39 ]. In a study investigating the genetic-and-epigenetic cell cycle network in HeLa cancer cells, methylation of HIST1H2AJ (among other genes) was found to result in cell proliferation and anti-apoptosis through NFκB, TGF-β, and PI3K/Akt/mTOR pathways[ 40 ]. HIST1H2AJ has not previously been highlighted as a gene of interest in HCC, which is a novel finding of our integrative analysis of methylation datasets.…”

TROAP regulates prostate cancer progression via the WNT3/survivin signalling pathways

“…The associated adhesion molecule complex consists of bystin, trophinin and TROAP, and bystin has been shown to be present in human PCa (5). In addition to its function as a component of the adhesion complex during embryo implantation, TROAP has also been reported to be required for spindle assembly during mitosis (6,7). It is also essential for centrosome integrity and proper bipolar organisation of spindle assembly during mitosis, playing an essential role in cell proliferation.…”