The Histone-H3K4-Specific Demethylase KDM5B Binds to Its Substrate and Product through Distinct PHD Fingers
Brianna J. Klein,
Lianhua Piao,
Yuanxin Xi,
Hector Rincon-Arano,
Scott B. Rothbart,
Danni Peng,
Hong Wen,
Connie Larson,
Xi Zhang,
Xia Zheng,
Michael A. Cortazar,
Pedro V. Peña,
Anthony Mangan,
David L. Bentley,
Brian D. Strahl,
Mark Groudine,
Wei Li,
Xiaobing Shi,
Tatiana G. Kutateladze
Affiliations
Brianna J. Klein
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Lianhua Piao
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Yuanxin Xi
Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Hector Rincon-Arano
Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Scott B. Rothbart
Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Danni Peng
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Hong Wen
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Connie Larson
Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
Xi Zhang
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Xia Zheng
Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Michael A. Cortazar
Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA
Pedro V. Peña
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Anthony Mangan
Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA
David L. Bentley
Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO 80045, USA
Brian D. Strahl
Department of Biochemistry and Biophysics and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Mark Groudine
Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Wei Li
Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Xiaobing Shi
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Tatiana G. Kutateladze
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA
The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation and is implicated in carcinogenesis. It contains multiple conserved chromatin-associated domains, including three PHD fingers of unknown function. Here, we show that the first and third, but not the second, PHD fingers of KDM5B possess histone binding activities. The PHD1 finger is highly specific for unmodified histone H3 (H3K4me0), whereas the PHD3 finger shows preference for the trimethylated histone mark H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for genes involved in inflammatory responses, cell proliferation, adhesion, and migration. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with the histone deacetylase 1 (HDAC1) in gene repression. KDM5B is downregulated in triple-negative breast cancer relative to estrogen-receptor-positive breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion, and the PHD1-H3K4me0 interaction is essential for inhibiting migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a multivalent mechanism for KDM5B-mediated transcriptional regulation.
