The PHD1 finger of KDM5B recognizes unmodified H3K4 during the demethylation of histone H3K4me2/3 by KDM5B.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC4225485 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chemotherapy is the main treatment for human cancers including gastric cancer. However, in response to chemotherapeutic drugs, tumor cells can develop drug resistance by reprogramming intracellular metabolic and epigenetic networks to maintain their intrinsic homeostasis. Previously, we have established cisplatin-resistant gastric cancer cells as a drug resistant model, and elucidated the XRCC1 as the core DNA repair mechanism of drug resistance. This study investigated the regulation of XRCC1 by lysine demethylase 5B (KDM5B) in drug resistance. We found that the methylation level of H3K4 decreased significantly in drug-resistant cells. The chemical inhibitor of H3K4 demethylases, JIB-04, restored the methylation of H3K4 and blocked the co-localization of XRCC1 and ?H2AX, eventually improved drug sensitivity. We further found that the expression level of KDM5B increased significantly in drug-resistant cells. Knockdown of KDM5B increased the methylation level of H3K4 and blocked the localization of XRCC1 to the DNA damage site, leads to increased drug sensitivity. In the sensitive cells, overexpression of KDM5B suppressed H3K4 methylation levels, which resulted to resistance to cisplatin. Moreover, we found that the posttranslational modification of KDM5B is responsible for its high expression in drug-resistant cells. Through mass spectrometry screening and co-immunoprecipitation validation, we found that the molecular chaperone HSP90 forms a complex with KDM5B in drug resistance cells. Interestingly, HSP90 inhibitor 17-AAG induced KDM5B degradation in a time-and-dose-dependent manner, indicating that HSP90 protected KDM5B from protein degradation. Targeting inhibition of HSP90 and KDM5B reversed drug resistance both in vitro and in vivo. Taken together, molecular chaperon HSP90 interacted with KDM5B to protect it from ubiquitin-dependent proteasomal degradation. Increased KDM5B demethylated H3K4 and facilitated the recruitment of XRCC1 to repair damaged DNA. Therefore, inhibition of HSP90 or KDM5B represented a novel approach to reverse chemoresistance in human cancers.
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Project description:Trophoblast stem (TS) cells derived from the trophectoderm (TE) of mammalian embryos have the ability to self-renew indefinitely or differentiate into fetal lineages of the placenta. Epigenetic control of gene expression plays an instrumental role in dictating the fate of TS cell self-renewal and differentiation. However, the roles of histone demethylases and activating histone modifications such as methylation of histone 3 lysine 4 (H3K4me3/me2) in regulating TS cell expression programs, and in priming the epigenetic landscape for trophoblast differentiation, are largely unknown. Here, we demonstrate that the H3K4 demethylase, KDM5B, regulates the H3K4 methylome and expression landscapes of TS cells. Depletion of KDM5B resulted in downregulation of TS cell self-renewal genes and upregulation of trophoblast-lineage genes, which was accompanied by altered H3K4 methylation. Moreover, we found that KDM5B resets the H3K4 methylation landscape during differentiation in the absence of the external self-renewal signal, FGF4, by removing H3K4 methylation from promoters of self-renewal genes, and of genes whose expression is enriched in TS cells. Altogether, our data indicate an epigenetic role for KDM5B in regulating H3K4 methylation in TS cells and during trophoblast differentiation.
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Project description:BackgroundPluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation. However, it remains unclear how H3K4 demethylation contributes to ES cell function.ResultsHere, we show that KDM5B, which demethylates lysine 4 of histone H3, co-localizes with H3K4me3 near promoters and enhancers of active genes in ES cells; its depletion leads to spreading of H3K4 methylation into gene bodies and enhancer shores, indicating that KDM5B functions to focus H3K4 methylation at promoters and enhancers. Spreading of H3K4 methylation to gene bodies and enhancer shores is linked to defects in gene expression programs and enhancer activity, respectively, during self-renewal and differentiation of KDM5B-depleted ES cells. KDM5B critically regulates H3K4 methylation at bivalent genes during differentiation in the absence of LIF or Oct4. We also show that KDM5B and LSD1, another H3K4 demethylase, co-regulate H3K4 methylation at active promoters but they retain distinct roles in demethylating gene body regions and bivalent genes.ConclusionsOur results provide global and functional insight into the role of KDM5B in regulating H3K4 methylation marks near promoters, gene bodies, and enhancers in ES cells and during differentiation.
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