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Epigenetic regulation of MMP-11 and -16 expression in human prostate cancer: the role of KDM6A.

Gokce Yildirim‐Buharalioglu,Recep İlhan,Yaren Çakmak,C. K. Buharalıoğlu

Published 2025 in Epigenomics

ABSTRACT

AIMS Matrix metalloproteinases (MMPs) promote prostate cancer (PCa) progression by degrading the extracellular matrix and enhancing metastasis. PCa is considered an "epigenetic catastrophe" due to disrupted histone modifications caused by chromatin-modifying enzyme dysregulation. We previously showed that lysine demethylase 6A (KDM6A) and 6B (KDM6B) are higher in metastatic PCa (LNCaP) versus benign prostatic hyperplasia (BPH-1). We investigated whether their elevation contributes to MMP upregulation. METHODS AND RESULTS LNCaP cells were treated with the KDM6 inhibitor GSK-J4, and mRNA levels of 23 MMPs were quantified by RT-qPCR. GSK-J4 reduced mRNA levels of 6 MMPs (MMP-7, -8, -11, -15, -16, and -19) out of 23. Decline in pre-spliced mRNA levels of MMP-7, -11, and -16 by GSK-J4 suggested transcriptional changes; only MMP-11 and -16 exhibited corresponding protein decreases. Among downregulated MMPs, MMP-7, -11, -15 and -16 mRNA were higher in LNCaP versus BPH-1, confirmed at protein level for MMP-11 and -16. KDM6A - but not KDM6B - siRNA reduced MMP-11 and -16 expression. GSK-J4 increased histone3 lysine27 trimethylation (H3K27me3) enrichment at MMP-11 and -16 promoters, as shown by Chromatin Immunoprecipitation (ChIP). CONCLUSION KDM6A demethylates H3K27me3 at MMP-11 and -16 promoters, sustaining their enhanced expression in PCa and revealing a novel epigenetic mechanism driving metastasis-associated protease expression.

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