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

[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 (H3K27me) enrichment at MMP-11 and -16 promoters, as shown by Chromatin Immunoprecipitation (ChIP).

[CONCLUSION] KDM6A demethylates H3K27me at MMP-11 and -16 promoters, sustaining their enhanced expression in PCa and revealing a novel epigenetic mechanism driving metastasis-associated protease expression.