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Am J Transl Res 2012;4(3):247-256
Original Article
Genomic amplification and a role in drug-resistance for the KDM5A
histone demethylase in breast cancer
Jinling Hou, Jack Wu, Alan Dombkowski, Kezhong Zhang, Andreana Holowatyj, Julie L Boerner, Zeng-Quan Yang
Karmanos Cancer Institute, Department of Oncology; Department of Pediatrics; Center for Molecular Medicine
and Genetics; Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, USA
Received April 13, 2012; accepted June 11, 2012; Epub July 22, 2012; Published August 15, 2012
Abstract: Lysine-specific demethylase 5A (KDM5A), an enzyme that removes activating H3K4 di- and
trimethylation marks, plays critical roles in controlling transcription and chromatin architecture, yet its biological
functions largely remain uncharacterized, particularly in the context of human cancer. In the present study, we
found that the KDM5A gene was significantly amplified and over-expressed in various human tumors, including
breast cancer. Reducing the expression of KDM5A by shRNA knockdown inhibited proliferation of
KDM5A-amplified breast cancer cells. More importantly, we demonstrated that KDM5A over-expression was
associated with breast cancer drug resistance. Furthermore, knockdown of KDM5A gene expression altered
H3K4 methylation and induced upregulation of CDK inhibitors as well as genes mediating apoptotic cell death.
Taken together, our study strongly links KDM5A histone demethylase activity to breast cancer proliferation and
drug resistance, and suggests KDM5A is a potential target for breast cancer therapy. (AJTR1204001).
Keywords: KDM5A, histone demethylases, gene amplification, drug-resistance
Address all correspondence to:
Dr. Zeng-Quan Yang
Karmanos Cancer Institute
4100 John R Street, HWCRC 815
Detroit, MI 48201, USA.
Tel: (313)576-8339; Fax: (313)576-8029
E-mail: yangz@karmanos.org
Original Article
Genomic amplification and a role in drug-resistance for the KDM5A
histone demethylase in breast cancer
Jinling Hou, Jack Wu, Alan Dombkowski, Kezhong Zhang, Andreana Holowatyj, Julie L Boerner, Zeng-Quan Yang
Karmanos Cancer Institute, Department of Oncology; Department of Pediatrics; Center for Molecular Medicine
and Genetics; Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, USA
Received April 13, 2012; accepted June 11, 2012; Epub July 22, 2012; Published August 15, 2012
Abstract: Lysine-specific demethylase 5A (KDM5A), an enzyme that removes activating H3K4 di- and
trimethylation marks, plays critical roles in controlling transcription and chromatin architecture, yet its biological
functions largely remain uncharacterized, particularly in the context of human cancer. In the present study, we
found that the KDM5A gene was significantly amplified and over-expressed in various human tumors, including
breast cancer. Reducing the expression of KDM5A by shRNA knockdown inhibited proliferation of
KDM5A-amplified breast cancer cells. More importantly, we demonstrated that KDM5A over-expression was
associated with breast cancer drug resistance. Furthermore, knockdown of KDM5A gene expression altered
H3K4 methylation and induced upregulation of CDK inhibitors as well as genes mediating apoptotic cell death.
Taken together, our study strongly links KDM5A histone demethylase activity to breast cancer proliferation and
drug resistance, and suggests KDM5A is a potential target for breast cancer therapy. (AJTR1204001).
Keywords: KDM5A, histone demethylases, gene amplification, drug-resistance
Address all correspondence to:
Dr. Zeng-Quan Yang
Karmanos Cancer Institute
4100 John R Street, HWCRC 815
Detroit, MI 48201, USA.
Tel: (313)576-8339; Fax: (313)576-8029
E-mail: yangz@karmanos.org
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