A comprehensive study on genome-wide coexpression network of KHDRBS1/Sam68 reveals its cancer and patient-specific association

Abstract

Human KHDRBS1/Sam68 is an oncogenic splicing factor involved in signal transduction and pre-mRNA splicing. We explored the molecular mechanism of KHDRBS1 to be a prognostic marker in four different cancers. Within specific cancer, including kidney renal papillary cell carcinoma (KIRP), lung adenocarcinoma (LUAD), acute myeloid leukemia (LAML), and ovarian cancer (OV), KHDRBS1 expression is heterogeneous and patient specific. In KIRP and LUAD, higher expression of KHDRBS1 affects the patient survival, but not in LAML and OV. Genome-wide coexpression analysis reveals genes and transcripts which are coexpressed with KHDRBS1 in KIRP and LUAD, form the functional modules which are majorly involved in cancer-specific events. However, in case of LAML and OV, such modules are absent. Irrespective of the higher expression of KHDRBS1, the significant divergence of its biological roles and prognostic value is due to its cancer-specific interaction partners and correlation networks. We conclude that rewiring of KHDRBS1 interactions in cancer is directly associated with patient prognosis.

Figure 1

Expression of KHDRBS1 mRNA in KIRP and LUAD: (A,B) mRNA expression in the healthy and cancerous tissue of KIRP & LUAD patients. (C,D) mRNA expression in adjacent healthy and cancer tissue from a same patient in KIRP & LUAD respectively (Error bar in each diagram represent the maximum and minimum value of RSEM normalized count. KIRP: kidney renal papillary cell carcinoma, LUAD: lung adenocarcinoma).

Figure 2

Patient specific expression of KHDRBS1, survival and correlation analysis: (A) Volcano plot summarizing the Z-score distribution of KHDRBS1expression in different cancer. (B–E) shows the difference in KHDRBS1 mRNA expression level in Z > 1 and Z < −1 sample in KIRP, LUAD, OV and LAML respectively (****P < 0.0001). (F–I) Kaplan-Meier curve shows the comparison of fraction survival in higher expression (Z > 1) and lower expression (Z < −1) group in all four cancer. In KIRP and LUAD, the higher expression of KHDRBS1 affects the patient survival (P < 0.05), whereas in OV and LAML there is no difference in patient survival (P > 0.05) in higher and lower expression group. (J) Boxplot summarizing the distribution of correlation coefficient of KHDRBS1 to all other genes (r_s > 0.3, P < 0.05). In boxplot, the median is indicated by the horizontal line dividing the interquartile range (Q25, Q75). Upper and lower ticks represent the maximum and minimum value (KIRP: kidney renal papillary cell carcinoma, LUAD: lung adenocarcinoma, LAML: acute myeloid leukemia, and OV: ovarian cancer).

Figure 3

Overlap of protein-protein interactions (PPI) dataset and coexpressed gene of Sam68/KHDRBS1 and processes and pathway enrichment analysis in different cancer: (A–D) Venn diagram and network figure shows the overlapping genes which coexpress and interact with Sam68/KHDRBS1in KIRP, LUAD, OV and LAML respectively. The bar diagram indicates the process and pathway enrichment analysis of overlapping gene in respective cancer. Logarithmic corrected p-values for significant overrepresentation are shown.

Figure 4

Distribution of functional similarities between the coexpressed genes in different cancer. The functional similarities between coexpressed genes (r_s > 0.3, p < 0.05) with KHDRBS1 is calculated based on GO semantic similarity. The random set of genes (Random) is used as negative control. The functional similarity is high in case of KIRP and LUAD compared to the OV, LAML and random set (n = 500) of genes (box boundaries represent the first and third quartile (Q.25, Q.75). The median is indicated by the horizontal line dividing the interquartile range. Upper and lower ticks represent the maximum and minimum value). Mann-Whitney test was performed separately in between KIRP vs. OV, LAML, Random and LUAD vs. OV, LAML, Random (***P < 0.001).

Figure 5

Relative expression of different KHDRBS1 transcript and process and pathway enrichment analysis of coexpressed target transcript of KHDRBS1/Sam68: (A) Transcript (uc001bua, uc001bub and uc001buc) structure of KHDRBS1 from UCSC database. (B–D,F) show the relative expression of uc001bua, uc001bub, and uc001buc transcript in KIRP, LUAD, OV, and LAML respectively (error bar represent the standard deviation). (F) Boxplot is summarizing the distribution of correlation coefficient of uc001bub with all other transcripts (r_s > 0.3, P < 0.05) in all four cancers. (G–J) Venn diagram representing overlapping coexpressed and target transcript of KHDRBS1/Sam68. The bar diagram indicates the process and pathway enrichment analysis of overlapping genes in specific cancer (Logarithmic corrected P-values for significant overrepresentation are shown).