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 with 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.

• Authors: Na Li, Shilpa S Dhar, Tsai-Yu Chen, Pu-Yeh Kan, Yongkun Wei, Jae-Hwan Kim, Chia-Hsin Chan, Hui-Kuan Lin, Mien-Chie Hung, Min Gyu Lee
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 4 Pg. 831-43 (Feb 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26747897 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Minor Histocompatibility Antigens
• Histone Demethylases
• KDM5D protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Histone Demethylases (genetics, metabolism)
• Humans
• Male
• Mice
• Minor Histocompatibility Antigens
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Prostatic Neoplasms (genetics, pathology)
• Transfection