Differential Expression of Hub Genes and Activation of p53 by Anti-cancer Compound Curaxin CBL0137

Abstract

Cancer is a global concern and there is a need for effective drugs. CBL0137 is a small water-soluble molecule and a new second-generation compound in the family of curaxins with potential anti-cancer activity. Curaxins in general, including CBL0137 intercalate into DNA, and act by targeting the histone chaperone ‘facilitates chromatin transcription’ (FACT) complex and have the potential to treat tumors by reducing the growth of cancer cells which is shown in a variety of cell lines and animal models. CBL0137 is found to activate the tumor suppressor gene p53. However, the mechanism of p53 activation is poorly understood. Utilizing bioinformatics analysis on available datasets of CBL0137 treated cancer cells of glioma, cervical and multiple myeloma, differentially expressed genes (DEGs) that may lead to the activation of p53 were examined. Three GEO datasets of cells treated with various concentrations of CBL0137 were analyzed, namely HSJD-DIPG007 (GSE153441), MM1.S (GSE117611) and HeLa S3 (GSE117611). The DEGs were identified based on p-values less than 0.05, logFC values greater than 1 and less than -1 and analyzed using GEO2R, Enrichr, and STRING, and data visualization was performed on Tableau. Compared to the controls, a total of 229, 1425, and 1005 genes were upregulated while 368, 2322, and 1673 genes were downregulated for HSJD-DIPG007, MM1.S and HeLa S3 datasets, respectively. Further collective analysis revealed a total of 38 common DEGs among the three datasets. Using Enrichr and STRING on these 38 DEGs, seven hub genes were obtained, SKP2, RGS16, CSRP2, CENPA, HJURP, DTL, and HEXIM1 with these possible mechanisms: inhibition of AKT phosphorylation by upregulated genes RGS16 and CSRP2, p300-mediated acetylation of p53 via SKP2, inhibition of MDM2 by DTL downregulation and HEXIM1 upregulation, and inhibition of AURKB via CENPA and HJURP downregulation. This study analyzed the three datasets and highlighted how these identified hub genes may play a role in leading to p53 activation by CBL0137. KEYWORDS: Curaxin; CBL0137; Differentially Expressed Genes; Cancer; p53; Glioblastoma; Cervical; Myeloma