Identifies KCTD5 as a novel cancer biomarker associated with programmed cell death and chemotherapy drug sensitivity

Abstract

Background: More and more studies have demonstrated that potassium channel tetramerization domain-containing 5 (KCTD5) plays an important role in the development of cancer, but there is a lack of comprehensive research on the biological function of this protein in pan-cancer. This study systematically analyzed the expression landscape of KCTD5 in terms of its correlations with tumor prognosis, the immune microenvironment, programmed cell death, and drug sensitivity.

Methods: We investigated a number of databases, including TCGA, GEPIA2, HPA, TISIDB, PrognoScan, GSCA, CellMiner, and TIMER2.0. The study evaluated the expression of KCTD5 in human tumors, as well as its prognostic value and its association with genomic alterations, the immune microenvironment, tumor-associated fibroblasts, functional enrichment analysis, and anticancer drug sensitivity. Real-time quantitative PCR and flow cytometry analysis were performed to determine the biological functions of KCTD5 in lung adenocarcinoma cells.

Results: The results indicated that KCTD5 is highly expressed in most cancers and that its expression is significantly correlated with tumor prognosis. Moreover, KCTD5 expression was related to the immune microenvironment, infiltration by cancer-associated fibroblasts, and the expression of immune-related genes. Functional enrichment analysis revealed that KCTD5 is associated with apoptosis, necroptosis, and other types of programmed cell death. In vitro experiments showed that knockdown of KCTD5 promoted apoptosis of A549 cells. Correlation analysis confirmed that KCTD5 was positively correlated with the expression of the anti-apoptotic genes Bcl-xL and Mcl-1. Additionally, KCTD5 was significantly associated with sensitivity to multiple antitumor drugs.

Conclusion: Our results suggest that KCTD5 is a potential molecular biomarker that can be used to predict patient prognosis, immunoreactions and drug sensitivity in pan-cancer. KCTD5 plays an important role in regulating programmed cell death, especially apoptosis.

Keywords: Cell apoptosis; Drug sensitivity; KCTD5; Pan-cancer; Prognosis; Tumor microenvironment.

Fig. 1

The expression landscape of KCTD5 in pan-cancer. A The expression level of KCTD5 in tumor tissues and adjacent normal tissues of 33 TCGA cancer from TCGA datasets. B The expression level of KCTD5 in different tumor tissues and corresponding normal tissues from TCGA and GTEx datasets. C The expression levels of KCTD5 in multiple tumor cell lines (HPA dataset). *P < 0.05; **P < 0.01; ***P < 0.001

Fig. 2

The correlation between KCTD5 expression and immune subtypes and molecular subtypes in pan-cancer. A Expression levels of KCTD5 in different immune subtypes. C1 (wound healing); C2 (IFN-gamma dominant); C3 (inflammatory); C4 (lymphocyte depleted); C5 (immunologically quiet); C6 (TGF-b dominant). B Expression levels of KCTD5 in different molecular subtypes

Fig. 3

The genetic alterations and DNA methylation of KCTD5 across cancers. A-C The change frequency of CNV in KCTD5 was revealed by GSCA database. Different colors in the pie chart represent different types of variation. Hete Amp (heterozygous amplification): CNV = 1; Hete Del (heterozygous deletion): CNV = -1. D-F The SNV classes of KCTD5 in pan-cancer. G The differential methylation analysis of KCTD5 in a variety of tumors. H The correlation analysis showed that the methylation level of KCTD5 was negatively correlated with mRNA expression

Fig. 4

Survival analysis of KCTD5 in pan-cancer. We assessed the prognostic value of KCTD5 in pan-cancer using the Kaplan–Meier plotter (A) and the PrognoScan (B, C) database. A, B Overall survival (OS) was used as an indicator. C The survival analysis including disease-free survival (DFS), disease-specific survival (DSS), distant metastasis-free survival (DMFS), and relapse-free survival (RFS) of KCTD5 in breast cancer

Fig. 5

Correlations between KCTD5 expression and immune modulators in pan-cancer. A The correlation between the expression of KCTD5 and the infiltration levels of different immune cell subtypes. B The expression of KCTD5 was significantly associated with the abundance of infiltrating immune cells

Fig. 6

Correlation analysis between KCTD5 expression and immune infiltration of cancer-associated fibroblasts (CAFs) in pan-cancer

Fig. 7

Correlation of KCTD5 and immunoregulation-related genes in pan-cancer. Correlations between KCTD5 expression and (A) Immunoinhibitors, B Immunostimulators, C MHC molecules, D Tumor-infiltrating lymphocytes (TILs), E Chemokines, F Chemokines receptors

Fig. 8

The signaling pathway analysis of KCTD5 in human cancers. A BRCA. B UCEC. C CESC. D COAD. E KIRC. F LIHC. G PAAD. H LUAD

Fig. 9

KCTD5 inhibited cell apoptosis in LUAD. A The mRNA expression of KCTD5 in lung cancer cells. B The siRNA effectively regulated the expression of KCTD5 in the A549 cell line. SCR, scrambled negative control; si, small interfering. C, D In A549, the apoptosis rate was significantly increased in the KCTD5 silenced group (siRNA-KCTD5) relative to the control group (SCR). E, F Correlation analysis revealed that KCTD5 was positively correlated with anti-apoptotic genes Bcl-xL and Mcl-1

Fig. 10

Drug sensitivity analysis based on KCTD5 expression using the three different databases CTRP (A), GDSC (B), Cellminer (C). P < 0.05 was considered statistically significant