Abstract
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 ofthe 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.
Original language | English (US) |
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Pages (from-to) | 325-335 |
Number of pages | 11 |
Journal | Cell reports |
Volume | 6 |
Issue number | 2 |
DOIs | |
State | Published - 2014 |
Funding
This work was supported by grants from the NIH (GM096863 and GM101664 to T.G.K., R01HG007538 to W.L., HL65440 to M.G., GM068088 to B.D.S., and GM063873 to D.L.B.), CPRIT (RP110471 to X.S. and W.L.), the Welch Foundation (G1719 to X.S.), and the American Cancer Society (RSG-13-290-01-TBE to X.S.). W.L. is a recipient of a Duncan Scholar Award, and X.S. is a recipient of a Kimmel Scholar Award. S.B.R. is a postdoctoral fellow of the American Cancer Society (PF-13-085-01-DMC). B.J.K. was supported by NIH Postdoctoral Training Grant T32AA007464 and is an American Heart Association postdoctoral fellow.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology