JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis

Abstract

Entire or partial deletions of the male-specific Y chromosome are associated with tumorigenesis, but whether any male-specific genes located on this chromosome play a tumor-suppressive role is unknown. Here, we report that the histone H3 lysine 4 (H3K4) demethylase JARID1D (also called KDM5D and SMCY), a male-specific protein, represses gene expression programs associated with cell invasiveness and suppresses the invasion of prostate cancer cells in vitro and in vivo. We found that JARID1D specifically repressed the invasion-associated genes MMP1, MMP2, MMP3, MMP7, and Slug by demethylating trimethyl H3K4, a gene-activating mark, at their promoters. Our additional results demonstrated that JARID1D levels were highly downregulated in metastatic prostate tumors compared to normal prostate tissues and primary prostate tumors. Furthermore, the JARID1D gene was frequently deleted in metastatic prostate tumors, and low JARID1D levels were associated with poor prognosis in prostate cancer patients. Taken together, these findings provide the first evidence that an epigenetic modifier expressed on the Y chromosome functions as an anti-invasion factor to suppress the progression of prostate cancer. Our results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer.

ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes

“…Because the cell migration assay measures only the migratory abilities of cells, we additionally examined the invasive abilities of cells using cell invasion assay in which cells digest and invade a Matrigel matrix that mimics the in vivo extracellular matrix. Similar to JARID1D knockdown ( Figures S1C and S1D ) (Li et al, 2016), ZMYND8 knockdown increased the invasiveness of DU145 and CWR22Rv1 cells ( Figures 3D, S1E, and S1F ).…”

“…Because our recent study has showed that JARID1D is an anti-invasive factor that acts against prostate cancer metastasis (Li et al, 2016), we determined whether ZMYND8 regulates cellular invasion using two androgen-independent and moderately invasive human prostate cancer cell lines DU145 and CWR22Rv1 (Nemeth et al, 1999; Sramkoski et al, 1999). ZMYND8 depletion using two independent shRNAs had a negligible effect on cell proliferation and migration abilities ( Figures 3A–3C ).…”

“…Our recent study has demonstrated that the H3K4 demethylase JARID1D is an anti-invasive factor that acts against prostate cancer metastasis (Li et al, 2016). In the present study, we sought to gain new insight into JARID1D-mediated gene regulation.…”

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression

“…KDM5D has been reported to have a tumor suppressor function in prostate cancer (23). Specifically, KDM5D regulates invasion-associated genes (such as the MMP family), demethylating their H3K4me3 marks, and loss of KDM5D causes the cell to acquire invasiveness with increased H3K4me3 levels in the promoter regions of relevant genes, leading to the development of metastasis.…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…JARID1B can also negatively regulate the malignant state mediated by genome-wide H3K4me3 hyper-methylation present in leukemias driven by the MLL methyltransferase [21]. Recently, JARID1D was shown to be a tumor suppressor based on its downregulation, mutation, or loss in prostate cancer [22] and CCRCC [23]. In hormone-sensitive prostate cancers, JARID1D directly interacts with the androgen receptor (AR) to attenuate the transcriptional activation of AR target genes.…”