miR-26a-5p restoration via EZH2 silencing blocks the IL-6/STAT3 axis to repress the growth of prostate cancer

ABSTRACT

Background

Interleukin-6 (IL-6) is involved in the activation of several oncogenic pathways in prostate cancer. However, its upstream trans-signaling pathway remains largely unknown. This work proposes a mechanistic explanation of IL-6’s upstream effectors in prostate carcinogenesis.

Research design & methods

Samples were harvested to validate the expression of EZH2, miR-26a-5p, and IL-6. Moreover, the protein and its phosphorylation of STAT3 (signal transducer and transcription activator 3) were assessed in prostate cancer cells. We explored the effects of these effectors on malignant phenotypes in vitro and tumor growth in vivo using functional assays. Bioinformatics analysis, dual-luciferase reporter gene assays, and chromatin immunoprecipitation (ChIP) assays were used to determine their binding relationships.

Results

Overexpression of EZH2 and IL-6, and under expression of miR-26a-5p was observed in prostate cancer. Silencing IL-6 repressed STAT3 to suppress the malignant phenotypes of prostate cancer cells. Mechanistically, EZH2 inhibited miR-26a-5p expression by promoting H3K27 histone methylation, and miR-26a-5p restricted the malignant phenotypes of prostate cancer by targeting IL-6. Ectopic EZH2 expression reduced xenograft growth by inhibiting miR-26a-5p and activating the IL-6/STAT3 axis.

Conclusion

EZH2 May potentially be involved in regulating its expression by recruiting H3K27me3 to the miR-26a-5p promoter region, which could further impact the IL6/STAT3 pathway.

KEYWORDS:

• EZH2
• prostate cancer
• miR-26a-5p
• IL-6/STAT3
• malignant phenotype
• xenograft growth

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Guofu Pang, Xiaoxu Yuan, and Jing Chu designed the study. Qiwei Nie, Xuling Zhang and Wenqiang Zhang collated the data, designed and developed the database, carried out data analyses, and produced the initial draft of the manuscript. Guofu Pang, Qiwei Nie, Xiaoxu Yuan, Wenqiang Zhang, and Long Huang contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Ethics approval and consent to participate

Written informed consent was obtained from all patients prior to the study. The study protocols were approved by the Ethics Committee of our Hospital (Grant No.2020LP00419) and were based on the ethical principles of the Declaration of Helsinki. The animal experiments were performed in strict accordance with the Guide for the Care and Use of Laboratory Animals. All animal experiments were approved by the Institutional Animal Care and Use Committee of our Hospital (Grant No.2020AE00031).

Data availability statement

The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding authors.

Additional information

Funding

The Project Supported by Guizhou Provincial Natural Science Foundation of China (Grant No.Guizhou Province-ZK [2023] General 243).