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. 2024 Feb 5;17(1):34.
doi: 10.1186/s13048-024-01358-8.

SETDB1 promotes progression through upregulation of SF3B4 expression and regulates the immunity in ovarian cancer

Hongjuan Yang #  1 , Lei Sui #  2 , Cuicui Cai  1 , Huijun Chu  1 , Yuchao Diao  3
Affiliations

SETDB1 promotes progression through upregulation of SF3B4 expression and regulates the immunity in ovarian cancer

Hongjuan Yang et al. J Ovarian Res. .

Abstract

Background: Ovarian cancer (OC) is the most lethal gynecologic malignant tumour. The mechanism promoting OC initiation and progression remains unclear. SET domain bifurcated histone lysine methyltransferase 1(SETDB1) acts as an oncogene in a variety of tumours. This study aims to explore the role of SETDB1 in OC.

Methods: GEO, TCGA, CSIOVDB and CPTAC databases jointly analysed SETDB1 mRNA and protein expression. Effect of SETDB1 expression on the clinical prognosis of OC patients was analysed through online Kaplan‒Meier plotter and CSIOVDB database. Then, the effect of SETDB1 in OC cells progression and mobility was examined using MTT, EdU, colony formation and transwell assay. Additionally, Cistrome DB database was used to visualize the binding of SETDB1 protein and splicing factor 3b subunit 4 (SF3B4) promoter, and dual-luciferase reporter gene assay was performed to confirm the interaction. Finally, bioinformatics analysis was employed to reveal the relationship between SETDB1 and the microenvironment of OC.

Results: In the present study, we found that SETDB1 was obviously upregulated in OC and its overexpression predicted poor prognosis of OC patients. Then, we verified that SETDB1 promoted the progression and motility of OC cells in vitro. Knockdown of SETDB1 had the opposite effect. Further research showed that SETDB1 acted as a transcription factor to activate SF3B4 expression. SF3B4 knockdown impaired the effect of SETDB1 to promote the proliferative capacity and motility of OC cells. Finally, the results of bioinformatics analysis confirmed that SETDB1 regulated the immune microenvironment of ovarian cancer.

Conclusion: SETDB1 promoted ovarian cancer progression by upregulating the expression of SF3B4 and inhibiting the tumour immunity. SETDB1 may be a promising prognostic and therapeutic marker for OC.

Keywords: Ovarian cancer; SETDB1; SF3B4; Transcription factor; Tumour immunity.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
SETDB1 is highly expressed in ovarian cancer and associated with poor prognosis. A SETDB1 mRNA expression in ovarian cancer and normal ovarian epithelial tissue from GSE18520. B SETDB1 mRNA expression in ovarian cancer stroma and normal ovary stroma from GSE40595. C SETDB1 mRNA expression in ovarian cancer and normal ovarian epithelial tissue from TCGA database. D, E SETDB1 protein expression in ovarian cancer and normal ovary tissue from CPTAC. F, G Expression of SETDB1 in different stages and grades of ovarian cancer from CSIOVDB database. H Expression of SETDB1 in pan-cancer. I, J Kaplan–Meier analysis showed the effect of SETDB1 expression on PFS or PPS of ovarian cancer patients from K-M plotter. K, L Kaplan–Meier analysis showed the effect of SETDB1 expression on OS or PFS of ovarian cancer patients from CSIOVDB
Fig. 2
Fig. 2
Overexpression and knockdown efficiency of SETDB1. A The efficiency of SF3B4 mRNA overexpression and knockdown was detected by qRT-PCR. B Up- and down-regulation efficiency of SETDB1 protein was confirmed by WB
Fig. 3
Fig. 3
SETDB1 promotes ovarian cancer cells proliferation in vitro. A, B MTT assay was performed to detect the impact of SETDB1 overexpression and knockdown on growth ability in ovarian cancer cells. C EdU assay was performed to analyze the proliferation of ovarian cancer cells upon SETDB1 knockdown. D Colony formation assay was performed to evaluate the effect of SETDB1 on clonality in ovarian cancer cells
Fig. 4
Fig. 4
SETDB1 promotes ovarian cancer cells mobility in vitro. A Transwell assay showed the effect of SETDB1 on migration ability in ovarian cancer cells. B The effect of invasion ability of HEY, A2780 and SKOV3 cells was showed after SETDB1 downregulated
Fig. 5
Fig. 5
SETDB1 promotes the expression of SF3B4 in ovarian cancer. A Cistrome DB data showed the binding peak of SETDB1 protein in the SF3B4 promoter region. B Visualization analysis of Cistrome project 2124 data by IGV showed the SETDB1 binding site in SF3B4 promoter. C TCGA-OV database showed the positive correlation between SETDB1 and SF3B4 mRNA expression in ovarian cancer. D, E qRT-PCR and WB showed the effect of SETDB1 knockdown on SF3B4 mRNA and protein expression in ovarian cancer. F Luciferase reporter assays showed the effect of SETDB1 on SF3B4 promoter in HEY cells
Fig. 6
Fig. 6
Knockdown of SF3B4 weakens the biological effects of SETDB1 overexpression in ovarian cancer cells. A MTT assay detected the effect of SETDB1 and SF3B4 different expression on proliferation in HEY cells. B, C Transwell assays showed the effect on migration and invasion ability of SF3B4 deficiency on SETDB1 stable-overexpressed HEY cells
Fig. 7
Fig. 7
SETDB1 methylation is amplified in ovarian cancer. A SETDB1 methylation amplification was found through MEXPRESS database in ovarian cancer. B The site of SETDB1 methylation amplification in ovarian cancer. C Relative SETDB1 expression upon TGF-β treatment
Fig. 8
Fig. 8
Overexpression of SETDB1 impairs the function of immune cells. A Heatmap showed correlation analysis between SETDB1 and immune cells in pan-cancer. B-F Correlation analysis between SETDB1 and abundance of B cells, CD4+ T cells, CD8+ T cells, macrophage and neutrophil in ovarian cancer
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