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Histone methyltransferase SUV39H2 regulates apoptosis and chemosensitivity in prostate cancer through AKT/FOXO signaling pathway

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Abstract

Prostate cancer (PCa) is one of the most common malignant tumors that exhibit both chemoresistance and recurrence. SUV39H2 is highly expressed in many types of human tumors, but its role in the development and progression of PCa has never been clarified. The aim of this study is to elucidate the role of SUV39H2 in the development and progression of PCa, its association with the AKT/FOXO signaling pathway, and its potential implications for PCa diagnosis and treatment. SUV39H2 expression was analyzed in The Cancer Genome Atlas (TCGA) and genotype tissue expression pan-cancer data. The TCGA database was evaluated for SUV39H2 enrichment and its correlation to immune cell infiltration. SUV39H2 levels in PCa tissues and control tissues were determined in 30 patients using qPCR and IHC. Clinical relevance was assessed via The Cancer Genome Atlas (TCGA). In vitro assessments including colony formation assays, Western Blot analysis, CCK-8 assays, and flow cytometry were utilized to establish SUV39H2’s contribution to PCa cell growth. The influence of SUV39H2 on PC3 and DU145 cell proliferation was assessed through a cell line-derived xenograft model. Sphere formation assays and qPCR were employed to delineate SUV39H2’s role in PCa stemness and chemosensitivity. In vitro macrophage polarization assays provided insights into SUV39H2’s association with M2 macrophages, while enrichment analysis shed light on its role in FOXO signaling. PCa tissues expressed higher levels of SUV39H2 than normal tissues. By knocking down SUV39H2, PCa cells were made more chemosensitive to docetaxel and cell proliferation and stemness were inhibited. Additionally, SUV39H2 knockdown significantly inhibited in vivo PCa cell growth and inhibited the polarization of macrophages. Furthermore, SUV39H2 was found to regulate AKT/FOXO signaling by increasing Akt and FOXO3a phosphorylation. Our findings highlight SUV39H2’s role in PCa cell apoptosis and chemosensitivity mainly by regulating the AKT/FOXO signaling pathway and suggest that SUV39H2 could be a potential target for PCa diagnosis and treatment.

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Acknowledgements

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Funding

This work was supported by Shenzhen Fundamental Research Program (Grant No. JCYJ20190808095615389).

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Author notes

  1. Donglin Sun, Jing Guo and Weifei Liang have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518100, China

    Donglin Sun & Xiangqiu Chen

  2. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510000, China

    Jing Guo, Yangxiao Chen & Shuqi Wei

  3. Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, 511500, Guangdong, China

    Weifei Liang

  4. Department of Clinical Medicine, The Second Clinical School of Guangzhou Medical University, Guangzhou, China

    Ai Li

  5. Nephrology Department, Southern Medical University Affiliated Longhua People’s Hospital, Shenzhen, China

    Li Wang

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  1. Donglin Sun
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Contributions

Conception and design: DS, XC, and LW; Administrative support: JG, XC, and WL; Provision of study materials or patients: XC; Collection and assembly of data: DS and XC; Data analysis and interpretation: SL, QL, QL, and YC; Manuscript writing: XC, YS, SY, and AL; Final approval of manuscript: All authors.

Corresponding authors

Correspondence to Li Wang or Xiangqiu Chen.

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The authors have no conflicts of interest to declare.

Ethical approval

PCa and paracancerous tissue specimens were taken after informed and written consent and the study was approved by the Ethics Committee of Shenzhen Hospital, Southern Medical University (Shenzhen, China). All animal procedures were conducted in compliance with the Guide for the Care and Use of Laboratory Animals (NIH Publications No.8023, revised 1978) and approved by the Institutional Biomedical Research Ethics Committee of Qingyuan People’s Hospital, and the study is reported in accordance with ARRIVE guidelines.

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Supplementary Figure 1

The Relationship between SUV39H2 Expression Level and Prognosis of Tumor Patients. a Forest plot of hazard ratios of SUV39H2 in 27 types of tumors. b Univariate and Multivariate Cox regression analyses regarding OS in prostate cancer. c The curve of risk score and Survival status of the patients. A higher risk score is associated with more deaths. Heatmap of the expression profiles of SUV39H2 prognostic genes in low- and high-risk group. d Kaplan–Meier survival analysis of SUV39H2. e Time-dependent ROC analysis

Supplementary file1 (TIF 104787 KB)

Supplementary Figure 2

Pan-cancer analysis of the correlation between SUV39H2 expression and immune checkpoint genes and immune regulators TMB and MSI. a Pan-cancer analysis of the correlation between SUV39H2 expression and immune checkpoint genes. b and c. Pan-cancer analysis of the correlation between SUV39H2 expression and immunomodulators TMB and MSI. *p <0.05, **p <0.01, and ***p <0.001

Supplementary file2 (PDF 466 KB)

Supplementary Figure 3 A–D

The correlation of SUV39H2 with infiltration of immune cells in the TCGA database

Supplementary file3 (TIF 5791 KB)

Supplementary file4 (DOCX 10 KB)

Supplementary file5 (DOCX 11 KB)

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Sun, D., Guo, J., Liang, W. et al. Histone methyltransferase SUV39H2 regulates apoptosis and chemosensitivity in prostate cancer through AKT/FOXO signaling pathway. Med Oncol 41, 44 (2024). https://doi.org/10.1007/s12032-023-02252-x

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